© 2001 by The Society for Integrative and Comparative Biology
Gaseous Transmission Across Time and Species1
1 The Whitney Laboratory, Department of Neuroscience, University of Florida, 9505 Ocean Shore Blvd, St. Augustine, Florida 32080-8610
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 SYNOPSIS GASES AS SIGNAL MOLECULESMULTIPLICITY OF NO SYNTHETIC...POTENTIAL NO-MEDIATED SIGNALING...NO SIGNALING IN LOWER...NO SIGNALING IN PLANTSTHE DISTRIBUTION AND FUNCTIONS...FUTURE DIRECTIONSReferences |
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This paper reviews comparative and evolutionary aspects of nitric oxide (NO) signaling in major systematic groups such as prokaryotes, plants, fungi and invertebrate animals. It appears that NO-mediated signaling can be as old as cellular organization itself. Both non-enzymatic and enzymatic (in addition to NOS) synthetic pathways can contribute to NO formation in living systems. The evolutionary roots of this means of gaseous signaling can be traced back to the role of NO in non-immune defensive mechanisms and the role of NO in control of gene expression, chemical ecology and, perhaps, symbiotic interactions in the ancient prokaryotic world. These functions of NO can be preserved in practically all modern taxons and be widely expressed in the nervous system. However, it is hypothesized that neuronal NO signaling is a relatively new evolutionary invention and it is likely to have happened several times during animal evolution. Although a comparative analysis of neuronal NO signaling is still in its early stages, the hypothesis is proposed that in many invertebrate lineages one of the primary neuronal functions of NO was regulation of feeding patterns, chemosensory processing and neurodevelopment.
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GASES AS SIGNAL MOLECULES |
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SYNOPSISGASES AS SIGNAL MOLECULESMULTIPLICITY OF NO SYNTHETIC...POTENTIAL NO-MEDIATED SIGNALING...NO SIGNALING IN LOWER...NO SIGNALING IN PLANTSTHE DISTRIBUTION AND FUNCTIONS...FUTURE DIRECTIONSReferences |
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The discovery that the gaseous radical nitric oxide (NO) is the major dilatory agent in the circulatory system of mammals (Ignarro et al., 1987
; Palmer et al., 1987; Moncada et al., 1991) immediately generated a burst of interest in the whole concept that living systems are able to produce and utilize gases as genuine intra- and extracellular signal molecules. Thus, in addition to various groups of hormones, signaling peptides and classical neurotransmitters, gaseous species are considered to be a new and distinct class of chemical messengers with potentially new and unique types of signaling mechanisms (Snyder et al., 1998). Specifically, the synthesis of NO does not require any special storage and transfer mechanism. NO can be released at the place of its initial synthesis and can diffuse across membrane barriers in 3D space, potentially affecting targets that are far from its origin (Wood and Garthwaite, 1994). NO primarily exerts its effects through direct covalent binding to target molecules resulting in their direct chemical modification (e.g., forming S-nitrosothiols or nitrosotyrosine residues in its target proteins [Stamler et al., 1992]). It appears that due to its physical and chemical properties, the concept of a NO microenvironment with transient NO gradients is a more accurate way to describe the actual situation in living tissues. Finally, being a radical, NO is chemically very active; NO gradients are dramatically affected by both the intracellular and extracellular redox state and, therefore, the biological half-life of NO can be extremely variable (from milliseconds to minutes and even hours) depending upon many environmental factors (such as the NO concentration itself, pO2, the presence of thiols, heme groups, or various endogenous scavengers, etc.). If we exclude the regulatory functions of oxygen and carbon dioxide, we might ask how many gases, in general, are endogenously produced in cells and tissues and are able to perform signaling functions? How different and unique are animals (versus plants, and other eukaryotic groups) with respect to the presence and distribution of these gaseous messengers? And, finally, how unique are vertebrates and chordates (versus various invertebrate phyla) with respect to gaseous signaling mechanisms?
The concept that gases can be endogenous intercellular messengers in living systems can be traced back to the 1900s (Thimann, 1974). It was shown that gaseous ethylene inhibits both growth and geotropism in plants, and ethylene is endogenously produced by fruits (reviewed by Thimann, 1974; Somerville, 2000). Further observations not only confirmed the crucial role of ethylene in plant development, but also provided a detailed analysis of its transduction mechanisms (Chang and Shockey, 1999). Surprisingly, there is strong evidence in one of the basal metazoan groups—sponges—that not only is ethylene produced, but that it is also involved in the regulation of calcium homeostasis (Krasko et al., 1999). Thus, these recent findings might radically change the commonly accepted opinion that signaling functions of ethylene are restricted to the plant kingdom only. Two other candidates (carbon monoxide [CO] and hydrogen sulfide [H2S]) have also been proposed as gaseous messengers in animal tissues (Dawson and Snyder, 1994; Abe and Kimura, 1996; Hosoki et al., 1997; Snyder et al., 1998; Gelperin et al., 2000). However, the roles and even the presence of biologically active concentrations of CO and H2S are questionable. On the other hand, the information related to NO signaling is overwhelming and, apart from ethylene in plants, NO is still the only confirmed player in the "class" of gaseous messengers in animals.
This signal molecule has widespread distribution among practically all animal groups, where it is involved in a countless number of biological phenomena (Moncada et al., 1991; Dawson and Snyder, 1994; Garthwaite and Boulton, 1995; Griffin and Stuehr, 1995; Moncada and Higgs, 1995; Snyder et al., 1998). Still, the comparative physiology and biochemistry of NO-mediated transmission pathways in practically all major invertebrate groups is poorly understood. Even now, the conditions that caused this versatile and yet potentially toxic molecule to evolve as a modulator of physiological processes in animal tissues are not yet apparent. Even now, the linkage of NO signaling functions between animal and non-animal groups is not established. The fact that NO was recently found in plants and was officially "rediscovered" by animal physiologists in prokaryotes where it acts not only as a transient intermediate in denitrification pathways, but also operates as a potential endogenous regulator of gene expression, suggests that there are deep phylogenetic roots for gaseous signaling. All together these data point out that NO-related regulatory mechanisms may be as old as cellular organization itself and the ‘ancestral’ functions of NO in primitive organisms are likely well preserved across four billion years of biological evolution.
Here, we would like to outline some functional analogies, which may provide insights on the trends in the evolution of NO signaling and its possible functional implications related to the origin of NO-dependent neuronal mechanisms. The lack of comparative data regarding the cloning of NO synthases (NOS) is a vital missing point and it substantially limits conjectures about evolution of NOS's themselves. Furthermore, the very limited physiological data on non-mammalian species create more speculations than testable hypotheses about evolution of NO signaling. Still, the basic principles of nitrogen metabolism in living cells including prokaryotes and lower eukaryotes are very similar. As a result, it might not be surprising that the major components of NO generating pathways would share a substantial level of similarity between phylogenetically distant animal groups, non-animal taxa and even prokaryotes. In this review article I purposely allow room for speculation, hoping to provoke new hypotheses and ideas leading to new comparative data.
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MULTIPLICITY OF NO SYNTHETIC PATHWAYS |
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SYNOPSISGASES AS SIGNAL MOLECULESMULTIPLICITY OF NO SYNTHETIC...POTENTIAL NO-MEDIATED SIGNALING...NO SIGNALING IN LOWER...NO SIGNALING IN PLANTSTHE DISTRIBUTION AND FUNCTIONS...FUTURE DIRECTIONSReferences |
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At least three pathways of enzymatic NO synthesis can be found in living systems. Alternatively NO can be produced non-enzymatically from nitrites in various cells and tissues and under certain chemical conditions.
Nitric Oxide Synthase (NOS): A "classical" enzymatic pathway in animals
In all animal tissues the enzymatic synthesis of NO proceeds according to the following reaction:
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Three groups of NOS isoforms catalyze the synthesis in mammalian tissues. All of them have been characterized biochemically and cloned from several mammalian species with numerous splicing variants (Griffin and Stuehr, 1995; Eissa et al., 1998; Stuehr, 1999; Wang et al., 1999). Two isoforms, neuronal NOS (nNOS; type I) and endothelial NOS (eNOS; type III), are Ca2+-dependent and constitutive isoforms (Knowles and Moncada, 1994). Ca2+ influxes associated with either ligand-gated or voltage activated Ca2+ channels up-regulate NOS activity and result in transient activation of NO synthesis, release of NO, and action on neighboring cells and neuronal terminals. On the contrary, inducible NOS (iNOS; type II) is a Ca2+-independent enzyme which normally cannot be detected in most tissues, but its expression is dramatically activated after appropriate stimulation (e.g., in the presence of lipopolysaccharides or in the response to potentially damaging stimuli; Griffin and Stuehr, 1995), resulting in a high and long-term activation of NO yield. iNOS is primarily involved in defense reactions and cytotoxicity (Nathan, 1992). Structurally, all NOSs consist of two major domains: the oxygenase or catalytic domain (i.e., N-terminal part of NOS with L-arginine, H4-biopterin and heme [Fe] binding sites) and the reductase domain (with FMN, FAD, and NADPH binding sites). The formation of dimers comprised of identical subunits is essential for NOS activity (Stuehr, 1999).
NOS enzymes have also been cloned from insects (Champagne et al., 1995; Regulski and Tully, 1995; Yuda et al., 1996; Nighorn et al., 1998) and molluscs (Korneev et al., 1998; Sadreyev et al., 2000); they all have greater sequence similarity to a constitutive neuronal-like NOS than to other isoforms (iNOS or eNOS) in vertebrates. It is interesting that, in contrast to vertebrate species which have three NOS genes, only one type of NOS isoform has been found in any given invertebrate species investigated so far.
On the other hand, no NOS genes were found among more than a dozen prokaryote/archaea species, or in yeasts, or in the flowering plant Arabidopsis thaliana, or in the nematode Caenorhabditis elegans where sequencing of the whole genome was completed. This situation implies the very interesting possibility that NOS first appeared in basal animal ancestor groups and then was lost in some animal taxa in the course of evolution. But, did NOS genes appear even earlier, before the origin of metazoan or unicellular animals? Can NOS genes themselves and related enzymes be present in plants, lower eukaryotes or even prokaryotes? It is still a possibility that NOS can be found in plants (other than Arabidopsis) and some non-animal eukaryotes, and even in prokaryotes. Still, the presence of endogenous NO does not always mean that it is produced by NOS. As it will be illustrated below, both non-enzymatic and NOS-independent enzymatic pathways might significantly contribute to NO formation. Additionally, we also ought to consider that L-arginine itself is a versatile amino acid involved in many metabolic pathways such as the urea cycle, and in the synthesis of polyamines, glutamate, creatine, and armatine, cellular bioenergetics, etc. (see Wu and Morris, 1998 for a recent review on L-arginine metabolism). Therefore, L-arginine-dependent L-citrulline formation (a widespread test for NOS activity) might occur via NOS-independent pathways, and extensive biochemical, pharmacological and molecular biological tests are required (especially for non-animal groups) to confirm the presence of NOS specific enzymes. For example, there is biochemical evidence for NOS-like enzymes in yeasts (Saccharomyces cerevisiae [Kanadia et al., 1998]) that have no recognizable NOS genes in their genome. Thus, in many comparative examples described below I will use the term "NOS-like" activity.
Prokaryotes
The only evidence for an NOS-like enzyme in prokaryotes came from the bacteria genus Nocardia. The enzyme was partially purified (the molecular mass of the homodimer protein is reported to be about 110 kD), and it was shown that it requires the same cosubstrates and cofactors as animal NOS (i.e., O2, NADPH, Ca2+, tetrahydrobiopterin [BH4], FMN and FAD). Moreover, NG-hydroxy-L-arginine was identified as an intermediate in L-citrulline formation. Finally, competitive inhibitors of mammalian NOS also suppress L-citrulline formation in Nocardia further suggesting the NOS-like activity (Chen and Rosazza, 1994, 1995). All these examples are extremely important for further analysis, since there were no NOS genes found in any prokaryotic genomes that were sequenced. Additionally, several prokaryotes have an uncharacterized gene in their genomes with high similarity to the oxygenase domain of NOS in animals. The predicted peptide potentially can be involved in NO synthesis, especially via interactions with other reductase related proteins in the cell. Theoretically, it is possible to imagine a situation where two major parts of NOS (the reductase and oxygenase domains) are products of two separate genes, but these peptides can functionally interact with each other with resulting NOS/or NOS-like enzymatic activity. The best way to test this hypothesis would be direct experiments with reconstruction of chimeric NOS enzymes in vitro (e.g., by combining the bacteria derived oxygenase domain and the mammalian reductase domain).
Fungi and plants
NOS-like activity (with the standard pharmacological and biochemical properties of mammalian NOS) was described in fungi (Werner-Felmayer et al., 1994; Ninnemann and Maier, 1996; Tao et al., 1996, 1997; Kanadia et al., 1998) and has been reported for plants (Cueto et al., 1996; Delledonne et al., 1998; Durner et al., 1998; Barroso et al., 1999; Caro and Puntarulo, 1999; Ribeiro et al., 1999). Proposed NO synthesis (i.e., L-arginine-L-citrulline conversion) in some plant tissues is Ca2+-dependent (Cueto et al., 1996; Delledonne et al., 1998; Barroso et al., 1999), whereas in others it is Ca2+-independent (Cueto et al., 1996), resembling the inducible type of NOS of mammals. Again, in view of the fact that NOS-like enzymes from non-animal tissues have neither been cloned nor purified, they have not been analyzed in detail. As a result any discussion of potential homology and similarity between these proteins and NOS in animals would be highly speculative. Yet again, I stress the interesting situation of claims for the presence of NOS activity but an absence of recognizable NOS genes in Arabidopsis.
The nitrogen cycle as the first enzymatic NO synthetic pathway?
In spite of the still controversial issue about the origin of NOS itself, there is strong evidence that gaseous NO was an important messenger in biological systems at the very dawn of evolution and it had (and still has) an important role in prokaryote bioenergetics. Indeed, NO is produced enzymatically in the so called nitrogen cycle. This cycle consists of nitrogen fixation (the reduction of molecular nitrogen to ammonia), nitrification (oxidation of ammonia into nitrates) and denitrification (the reduction of nitrates to other nitrogen oxides, including NO, and back to N2). The denitrification and associated NO formation initially found in prokaryotes was recently discovered in lower eukaryotes such as fungi (Shoun et al., 1992; Kobayashi and Shoun, 1995; Kobayashi et al., 1996) and higher plants (Dean and Harper, 1988; Payne et al., 1997).
Major details of the nitrogen cycle pathways are well known (Zumft, 1993; Hollocher and Hibbs, 1996; Payne et al., 1997; Zumft, 1997; Ferguson, 1998). Briefly, NO is produced from nitrites by two kinds of nitrite reductases, and NO itself can be further reduced to N2O by NO reductases or by NO dioxigenase (Gardner et al., 1998). The heme-containing enzymes involved in bacterial denitrification pathways are quite distinct from mammalian NOS. Even so, new discoveries of denitrification in fungi may shed light on the potential links between denitrification pathways and the ancestral NO synthase-like enzyme. Nitrite reductase from the fungus Fusarium oxysporum is similar to the Cu-type of the enzyme in Gram-positive bacteria, but it is located in the intermembrane space of the mitochondrion, in an area which is considered to be analogous to the periplasmic space in bacteria. This enzyme seems to be involved in anaerobic ATP production. Primitive denitrifying bacteria (similar to the extant Paracoccus denitrificans) can be considered as a common ancestral symbiotic prototype of the eukaryotic mitochondrion. One can speculate, therefore, that in primitive eukaryotes, mitochondria can still preserve their denitrifying capabilities and even their associated respiratory functions, whereas more "advanced" groups have lost this capacity in the course of evolution (see Kobayashi et al., 1996). It is interesting that apparent NOS was recently found in mammalian mitochondria (Guilivi et al., 1998; Tatoyan and Guilivi, 1998).
The next enzyme in the denitrification pathway of Fusarium—NO reductase—is a unique cytochrome P450 type protein (Park et al., 1997). Similar P450 types of NO reductase have been discovered in other fungi, such as Cylindrocarpon tonkinese (Usuda et al., 1995; Kobayashi et al., 1996), Streptomyces thioluteus (Shoun et al., 1998), and the yeasts Trichosporon cutaneum, Fellomyces fuzhounensis and Candida sp. (Tsuruta et al., 1998). Cytochrome P450 reductase is the only known enzyme group that shares substantial homology to all isoforms of the mammalian NOS (Bredt et al., 1991b; Stuehr, 1999). More specifically, cytochrome P450 reductase seems to be homologous to a distinct reductase domain, representing about half of a NOS protein; the second, N-terminal part of NOS (the oxygenase domain) has no apparent homologs in any presently available eukaryotic database.
A potential third mechanism (in addition to NOS and the denitrification pathways) of enzymatic NO synthesis in biological systems is also related to bioenergetics and the mitochondrion. For example, in mammalian tissues under anaerobic conditions mitochondrial cytochrome c oxidase and some other heme-containing proteins can contribute to reduction of nitrites to NO (Walters and Taylor, 1965; Meyer, 1973; Doyle et al., 1981).
Abiotic reduction of nitrites results in non-enzymatic NO formation
The requirement of an enzyme for NO synthesis in biological systems is not absolute. The fact that NO can be generated non-enzymatically (without NOS or denitrification pathways) from a nitrite solution is crucial for any comparative and evolutionary analysis of NO synthesis and signaling. In reality, abiotic NO formation is well known from the chemistry of NOx species, but until recently it was not considered to be an endogenous source of NO in animals.
The chemistry of NO oxidation is very complex, with many transient nitrogen/oxygen species (for details see Kharitonov et al., 1994, 1995; Saran and Bors, 1994; Wink et al., 1996b, Wink and Mitchell, 1998), where nitrites (NO2–) and nitrates (NO3–) are major sequential products of NO oxidation. In tissues, hemoproteins convert NO and NO2– to NO3– (Ignarro et al., 1993; Grisham et al., 1996). However, NO2– is the only stable product formed by the spontaneous oxidation of NO in oxygenated solutions (Ignarro et al., 1993; Kharitonov et al., 1994; Lewis and Deen, 1994).
In an acidic environment nitrites are easily converted to NO according to the equation:
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Again, the actual mechanisms are more complicated (for details see Kharitonov et al., 1994; Lewis and Deen, 1994; Saran and Bors, 1994; Butler et al., 1995; Feelisch and Stamler, 1996; Wink et al., 1996b; Wink and Mitchell, 1998), but without describing secondary pathways, the sequence can be presented as follows:
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Ascorbate (Mirvish et al., 1972; Archer et al., 1975) and some reducing compounds, such as NADPH, L-cysteine, reduced gluthatione and other thiols, have been reported to stimulate NO formation from nitrites (Feelisch and Noack, 1987; Feelisch, 1991, 1993; Scorza et al., 1997).
Non-enzymatic NO production from dietary nitrates in vivo was originally demonstrated in the human oral cavity (Duncan et al., 1995) and in the gut (Benjamin, 1994). In both cases NO concentrations were sufficient to be involved in primary non-immune defense reactions and, probably, in the control of digestive functions, such as mucosal blood flow, motility, and possibly secretion and absorption (Benjamin, 1994; Duncan et al., 1997). Estimated nitrite concentrations were between 0.1–100 µM in different parts of the digestive system, approaching a concentration of 1 mM in saliva following a high nitrate/nitrite test meal (Duncan et al., 1995). Similarly, non-enzymatic NO formation has been demonstrated in human skin (Weller et al., 1996), with a suggested physiological role in the inhibition of infection by pathogenic microscopic fungi, as well as in the modulation of cutaneous T-cell function, skin blood flow, and keratinocyte differentiation. The last function was independently confirmed by Vallette et al. (Vallette et al., 1998).
Large quantities of NO (similar to, or even higher than, those produced by NOS) can be formed in ischemic heart tissues by a mechanism that is not enzyme dependent and is not blocked by inhibitors of NOS (Zweier et al., 1995a, b). The authors conclude that this NO formation is a consequence of acidification, which serves to reduce the large pool of nitrites present within tissue. The mean nitrite concentration of the ischemic myocardium (12 µM) is sufficient to generate the detected amount of NO. It was concluded that enzyme-independent NO formation not only contributes to the process of postischemic injury, but also eliminates the protective effect of NOS inhibitors (Zweier et al., 1995b).
Non-enzymatic NO formation: Nitrite photolysis
Potentially, nitrite photolysis is another non-enzymatic, but biologically relevant, chemical process associated with NO signaling. Photochemical generation of NO from nitrites is a notable component of the nitrogen cycle in the Earth's biosphere. Nitrite absorbs maximally at 356 nm, and the process can be presented as follows (Zafiriou et al., 1980):
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The reaction occurs naturally in the surface layers of the world's oceans, predominantly in the central equatorial areas. NO formed by this mechanism may play an important role in marine ecosystems, and must be considered as an NO source to the atmosphere (Zafiriou et al., 1980). The measured partial pressure of NO in the air was less than 8 x 10–12 atm compared with a PNO calculated for surface seawater of 7 x 10–8 atm (McFarland et al., 1979). The estimated concentrations of NO in the surface film of tropical waters depends strongly on the nitrite distribution; they could be in the subnanomolar or nanomolar range during the day, dropping to a practically undetectable level after sunset. Nitrites (and, likely, NO) are important endogenous regulators of the biological clocks in the unicellular dinoflagellate Goniaulax polyedra (Roenneberg and Rehman, 1996). One might therefore speculate that the involvement of NO in the regulation of circadian rhythm, observed in higher animals (Ding et al., 1994), might be traced back to the earlier day-night conditions in the ancient oceanic waters.
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POTENTIAL NO-MEDIATED SIGNALING IN PROKARYOTES |
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SYNOPSISGASES AS SIGNAL MOLECULESMULTIPLICITY OF NO SYNTHETIC...POTENTIAL NO-MEDIATED SIGNALING...NO SIGNALING IN LOWER...NO SIGNALING IN PLANTSTHE DISTRIBUTION AND FUNCTIONS...FUTURE DIRECTIONSReferences |
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Although early data suggested that NO produced during denitrification pathways is no more than a short lived transient intermediate, denitrifying bacteria can release this gas extracellularly (e.g., to the soil; Yoshinari, 1993
), with subsequent accumulation that can be large enough to affect the functions of other target cells (both prokaryotes and eukaryotes). The measured steady-state NO extracellular concentrations during denitrification are 1–65 nM, comparable to those proposed for mammalian tissues; values as high as 0.5 µM were calculated for intracellular NO (Goretski et al., 1990). These concentrations of NO can have potentially cytostatic, and even cytotoxic, effects and could therefore be the components of natural defense mechanisms between various organisms. On the other hand, NO produced endogenously by some prokaryotes seems to be involved in true signaling pathways. For example, in Rhodobacter, NO up-regulates the expression of certain genes related to NO metabolism (Kwiatkowski and Shapleigh, 1996). No induction of these genes was observed with either cAMP or cGMP analogs, suggesting that NO-mediated effects were cyclic nucleotide independent. In a related Rhodobacter species that has no nitrite reductase and, therefore, is not able to make NO on its own, exogenously applied NO also regulates transcription of selected genes (Kwiatkowski et al., 1997). Indeed, this finding proves that NO produced by other bacteria can serve as a genuine intercellular messenger. In particular, NO is a good candidate for the type of pheromone that is involved in symbiotic interactions; and this role may not be restricted to the prokaryotic world only. One might also suggest that in this manner NO could also contribute to the symbiotic assembly of eukaryotic cells. This hypothesis would be difficult to test, but it would be important to analyze the role NO plays in symbiotic interactions among various eukaryotic groups as well as in plastide/cell relationships. Additionally, both pathogenic and symbiotic denitrifying bacteria in higher eukaryotes can significantly contribute to a pool of endogenous NO produced by NOS in the host as well as be an important factor in parasite-host interactions. |
NO SIGNALING IN LOWER EUKARYOTES |
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SYNOPSISGASES AS SIGNAL MOLECULESMULTIPLICITY OF NO SYNTHETIC...POTENTIAL NO-MEDIATED SIGNALING...NO SIGNALING IN LOWER...NO SIGNALING IN PLANTSTHE DISTRIBUTION AND FUNCTIONS...FUTURE DIRECTIONSReferences |
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As prokaryotes, fungal cells can generate NO as an intermediate in the denitrification process. In some species (e.g., Fusarium and Cylindrocarpon), nitrite and nitrate reduction is strongly coupled to the anaerobic synthesis of ATP with relatively high energy yields (Kobayashi et al., 1996
). In others, NO production is associated with NOS-like enzymes involved in the regulation of morphogenesis and development.
In the fungus Neurospora, NO suppresses light-induced conidial differentiation (Ninnemann and Maier, 1996). NOS inhibitors stimulate conidiation in the same way that light does, and they are highly effective both in darkness and in the light. The light treatment itself decreased cGMP levels (Ninnemann and Maier, 1996). Thus, it was hypothesized that, in darkness, a higher NOS activity could raise the intracellular cGMP. It is interesting that both in vertebrates and invertebrates NO/NOS systems are present in the retina and visual pathways.
In another eukaryotic group, mycetozoa or slime molds (Dictyostelium and Physarum), nutritional starvation causes a cascade of processes resulting in the arrest of cell growth, then the initiation of cell aggregation and differentiation. Endogenous NO produced during the initial phase of the developmental cycle can prevent the initiation of the cAMP pulses (cAMP acts as an intercellular chemotactic signal for the unicellular amoebae and triggers their aggregation). Therefore, NO has a negative effect on the aggregation (Tao et al., 1996, 1997). In accordance with this hypothesis, the presence of glucose increases NO production, whereas NO-scavengers, the NOS inhibitor L-NIO, and glucose deprivation facilitate the aggregation. Furthermore, NO generated in the interphase period prevents the adenylyl cyclase from producing cAMP, but does not alter cAMP receptor-stimulated activity in Dictyostelium. It was shown that NO can suppress glycolysis by selective modification of GAPDH (glyceraldehyde-3-phosphate dehydrogenase) via an ADP-ribosylation mechanism (Tao et al., 1997). Since NO production is Ca-independent, Tao et al. (1997) speculated that Dictyostelium expresses inducible-like type NOS. Although cGMP-producing enzymes were demonstrated in this species, NO failed to activate soluble guanylyl cyclase or alter the intracellular cGMP level.
Data related to the role of NO in different protozoa are in their initial state. There is a report that NO is involved in control of the cell cycle of the infusorians Tetrachimena termophila (Christensen et al., 1996). In a parasitic euglenozoan kinetoplastid, Trypanosoma cruzi, NO was shown to activate both locomotion and guanylyl cyclase activity. The effects were mimicked by L-arginine, L-glutamate and NMDA, which were also shown to up-regulate endogenous NOS and intracellular cGMP. The motility of the parasite was also enhanced by a cGMP analog and blocked by a competitive NOS inhibitor, suggesting that NO- and GMP-dependent pathways controlling a locomotory behavior are coupled (Pereira et al., 1997). Putative NOS has been partially purified from soluble extracts of Trypanosoma. The enzyme is Ca2+/calmodulin-dependent and requires NADPH, tetrahydrobiopterin, and FAD as co-factors (Paveto et al., 1995).
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NO SIGNALING IN PLANTS |
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SYNOPSISGASES AS SIGNAL MOLECULESMULTIPLICITY OF NO SYNTHETIC...POTENTIAL NO-MEDIATED SIGNALING...NO SIGNALING IN LOWER...NO SIGNALING IN PLANTSTHE DISTRIBUTION AND FUNCTIONS...FUTURE DIRECTIONSReferences |
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Regardless of possible mechanisms of NO synthesis in plant tissues (see above) they can encounter NO produced by symbiotic microorganisms in soil, as well as NO produced non-enzymatically from nitrites. In addition, nitrite and nitrate reductases can yield high nanomolar concentrations of NO (up to 800 nM) in higher plants (Yamasaki et al., 1999
; Yamasaki and Sakihama, 2000) in NADH-dependent reactions similar to denitrification pathways in prokaryotes. Again, disregarding the source of NO, the cytotoxicity and associated non-immune defense against various infections is one of the most well-confirmed functions of NO in plant tissues. It was demonstrated that NO is able to inhibit cytochrome oxidase in plant mitochondria (Millar and Day, 1996) and, therefore, contributes to both non-specific toxicity and the regulation of cellular respiration. The role of NO in plant immunity was established in two model plant preparations: tobacco cells and soybean cells (Delledonne et al., 1998; Durner et al., 1998). NO enhances the resistance of tobacco cells to viral infection by selective induction of defense-related genes (Durner et al., 1998). Remarkably, these genes are also induced by cGMP and cyclic ADP ribose; the latter can release Ca2+ from intracellular stores via ryanodyne-like receptors. Furthermore, the pathogen-stimulated NOS is associated with cGMP transients. In Arabidopsis, bacterial pathogens trigger rapid and localized cell death, a hypersensitive apoptosis-like response associated with the production of superoxide (O2–) and hydrogen peroxide (H2O2). The hypersensitive response plays an important role in plant defense mechanisms, limiting the spread of the infection. NO both potentiates the induction of hypersensitive cell death and leads to transcriptional activation of defense genes crucial for other immune reactions. In contrast, inhibitors of NOS promote disease and bacterial growth (Delledonne et al., 1998).
NOS-like enzymatic activity observed in the roots of the legume Lupinus albus was Ca2+-dependent, whereas such dependence was not observed in the nodules (Cueto et al., 1996). Thus, the authors speculated that the Ca2+-independent NOS in the nodules could be induced by liposaccharides from the symbiont Rhizobium, and thus has a role in the formation of new plant nodules caused by bacterial infection. Incidentally, the putative NOS activity in Lupinus is also located in phloem cells, a recognized signal transport system. Therefore, the signaling functions of NO in plants might be even more widespread and be used for long distance communications.
In summary, even the initial data on the functional role of NO in non-animal groups suggests that the phylogenetic roots for the major recognized functions of NO in mammals—non-immune defense systems and regulation of gene expression and differentiation—can be traced back to the prokaryotic world through well preserved mechanisms that persist in various non-metazoan eukaryotes such as protozoans, plants and fungi. It is logical to assume that the same basic functions of NO (well documented in practically all major invertebrate and vertebrate groups) might serve as key points for discussion of the origin and evolution of NO-dependent mechanisms in the animal kingdom.
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THE DISTRIBUTION AND FUNCTIONS OF NO SIGNALING IN INVERTEBRATE ANIMALS |
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SYNOPSISGASES AS SIGNAL MOLECULESMULTIPLICITY OF NO SYNTHETIC...POTENTIAL NO-MEDIATED SIGNALING...NO SIGNALING IN LOWER...NO SIGNALING IN PLANTSTHE DISTRIBUTION AND FUNCTIONS...FUTURE DIRECTIONSReferences |
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Many taxa crucial for evolutionary analysis either have not been studied (i.e., placozoans, sponges, lower chordates) or have not been investigated in sufficient detail (e.g., cnidarians, flatworms, nematodes). At present, information about NO signaling is mainly restricted to representatives of two relatively advanced groups: arthropods and molluscs (see also recent reviews; Martinez, 1995
; Moroz and Gillette, 1996; Jacklet, 1997; Muller, 1997; Bicker, 1998; Colasanti and Venturini, 1998; Moroz et al., 1999; Moroz, 2000a; and this issue). However, even in these two well-studied phyla, one can find practically all major NO functions described for mammals. A more complicated question is how many NOS producing enzymes/isoforms can be found in invertebrate animals? Three isoforms exist in mammals (and probably in most of the vertebrates), but only one type of NOS has been described so far in invertebrates, suggesting that both neuronal and non-neuronal NO signaling functions can be associated with one type of NOS. The complete sequencing of the genome in Drosophila also reveals the presence of only one NOS isoform (a constitutive enzyme), but we found two NOS isoforms in a mollusc, Aplysia californica (Sadreyev, Panchin, Moroz, unpublished observations).
Non-neuronal functions of NO such as various defense mechanisms, cytotoxicity and effects on development also seem to have been well conserved during animal evolution, and would likely be observed in representatives of all major phyla (Moroz, 2000b). On the other hand, the involvement of NO in neuronal signaling and the distribution of putative NOS-containing (nitrergic) neurons are difficult to predict from the existing data. Can NO be found in the nervous systems of all invertebrate groups, or is neuronal signaling via NO a relatively new invention characteristic of higher invertebrate phyla?
Among metazoa, cnidarians (jellyfishes, polyps, sea anemones and corals) have the most basal neuronal organization, which is considered to be closely related to the earliest nervous systems. The initial screening for NOS, with the NADPH-diaphorase technique (as a histochemical marker for NOS, see Bredt et al., 1991a; Dawson et al., 1991; Hope et al., 1991) failed to demonstrate a neuronal location for NOS in cnidarians (Elofsson et al., 1993). In contrast, selected non-neuronal tissues in various coelenterates showed prominent NADPH-d reactivity. Recently we continued this screening, testing more than 20 other cnidarian species. In most cases, we again failed to detect neuronal location of NOS-like enzyme activity. But there were two possible exceptions: the holoplanktonic hydromedusa Aglantha digitale (Moroz et al., 1997) and the scyphoid medusae Aurelia aurita (Moroz, 1999). In Aglantha, putative NOS-containing/NADPH-d reactive sensory-motor neurons are located in the tentacles where NO activates a cGMP-dependent type of locomotion characteristic of the feeding behavior in jellyfish (Moroz et al., 1997). In the other jellyfish, Aurelia, putative nitrergic neurons were located in the rhopalia (specialized sensory structures at the edge of the umbrella), but their functions are unknown.
Although NADPH-d histochemistry did not reveal any neuronal staining in the freshwater polyp Hydra (Elofsson et al., 1993), NO is involved in the initiation of feeding patterns (Colasanti et al., 1995; Colasanti et al., 1997). The presence of a Ca2+-dependent NOS-like enzyme was also demonstrated in biochemical experiments on both Hydra (Colasanti et al., 1997) and an anthozoan Aiptasia (Salleo et al., 1996). In Aiptasia, Salleo et al. (1996) proposed that a non-neuronal NOS is involved in defense reactions associated with the induction of Ca2+-dependent nematocyst discharges by stimulated acontia. Our recent cloning of NOS from a soft coral Discosoma (Panchin, Sadreyev, Moroz, unpublished data) confirms the presence of the NOS gene in cnidarians.
Evidence for the neuronal localization of NOS in other groups of invertebrates such as flat worms and nematodes is also contradictory. The localization of NOS/NADPH-d activity in neurons was demonstrated in flatworms (e.g., the freshwater planarian Dugesia tigrina [Eriksson, 1996], a tapeworm Hymenolepis diminuta [Gustafsson et al., 1996 Terenina et al., 2000], Schistosoma mansoni [Kohn et al., 2001] Mesocestoides vogae [Terenina et al., 1999], Diphyllobothrium dentriticum [Lindholm et al., 1998], filariids Brugia [Kaiser et al., 1998; Pfarr and Fuhrman, 2000]), and in the parasitic nematode Ascaris suum (Bascal et al., 1995, 1996), but not in the free-living C. elegans (Elofsson et al., 1993). Screening of the completed genome in C. elegans also failed to detect the presence of NOS genes. A non-neuronal location of fixative-resistant NADPH-d activity was observed in many plathyhelmintes.
As it stands today, putative nitrergic (NOS-releasing) neurons occur in some invertebrate groups, but not in others. Thus, two scenarios with respect to the participation of NO in neuronal signaling could be suggested: (i) NOS was present in the nervous system of a basal animal group, but it was lost in some taxa (such as in the nematode C. elegans); (ii) involvement of NOS in neuronal signaling occurred independently in different groups and many times in evolution; therefore, the "lower" invertebrate groups may represent transient stages of this process. More advanced invertebrate groups express both neuronal and non-neuronal localization of NOS.
Apart from the widely distributed role of NO in defensive and developmental mechanisms, are there any characteristic neuronal-specific or behavioral functions mediated by NO? Taken together, the data on various invertebrates (see Moroz, 2000b) suggest that at least two neuronal functions of NO are highly conserved across the major phyla. These functions are: (i) the involvement of NO in sensory processing, particularly in chemosensory and olfactory systems; and (ii) the involvement of NO in the control of feeding. For example, NO donors selectively activate feeding motor patterns in representatives of phylogenetically very distant animal groups such as the various molluscs Lymnaea (Moroz et al., 1993; Elphick et al., 1995), Pleurobranchaea, Tritonia (unpublished observations), Clione (Moroz et al., 2000), and cnidarians (Aglantha; Moroz et al., 1997). Recent comparative studies on vertebrates, including mammals, provide additional support to the idea that NO is a ubiquitous messenger in feeding systems. A role for NO in chemosensory processing also can be found in representatives of such diverse phyla as molluscs, arthropods, chordates (vertebrates) and some cnidarians (see review Moroz, 2000b).
Hypothetical trends in the evolution of NO signaling
The presence of NO signaling in both prokaryotes and eukaryotes strongly suggests that NO may have played a crucial role in the early stages of the evolution of life (Moncada and Martin, 1993; Feelisch and Martin, 1995; Franchini et al., 1995; Durner et al., 1999; Liu et al., 2000). The radical nature and the presence of different redox forms of NO would contribute significantly to the omnipresent characteristics of NO-dependent mechanisms. All functions of NO also appear to be closely related and to interact with each other (Fig. 1). As a result, many physiological and pathophysiological features of NO can be derived from its two major functional activities: non-immune defense and intra- and intercellular signaling; transformations between these functions are primarily determined by local steady-state concentrations of NO.
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The origins of these two functions might be traceable to the very first primordial protocells. Even in the prokaryotic world, both the cytotoxic and the signaling characteristics of NO-mediated pathways might exist and contribute to intracellular communication and symbiotic interactions. The role of NO in development and aggregation in higher eukaryotes might also be traced back to the origin of multicellular organization, and, probably, to the very dawn of the eukaryotic organization itself. NO could be a good candidate to contribute to the symbiotic assembly of the eukaryotic cell. Since the origin of the eukaryotes can be associated with the rise of oxygen in the Earth's atmosphere more than 2 billion years ago, NO might also have an important antioxidant/protective function as a scavenger of oxygen radicals (specifically the superoxide anion radical), which arise as byproducts of oxygen metabolism and cell respiration (Feelisch and Martin, 1995
; Liu et al., 2000). Present comparative data are not sufficient to make any reasonable speculation about the origin and genealogy of the NOS enzyme itself, or about evolutionary relationships between different NOS isoforms (i.e., inducible iNOS vs. constitutive nNOS). Both isoforms can be present in a variety of tissues and both can be good candidates for the ancestral prototype of NOS. Although a neuronal-like NOS was identified as the only NOS isoform found in molluscs and in insects, it might be derived from an inducible-like prototype of NOS, since the iNOS gene is smaller and lacks a few domains characteristic of nNOS. The hypothesis can be supported if NOS cloned from cnidaria and sponges is shown to be homologous with iNOS isoforms.
The evolutionary origin of NOS itself can be reconstructed as a result of the fusion of two initially independent genes: one corresponding to the NOS's reductase domain (and homologous to cytochrome P450 reductase) and the second corresponding to the NOS's oxygenase domain (found as a separate gene in several bacteria).
Regardless of evolutionary relationships between NOS isoforms, the specific involvement of NO in neuronal signaling seems to be a relatively new evolutionary invention. It might well be that neuronal NOS and nitrergic neurons evolved independently in different invertebrate groups. Thus, at first glance, the somewhat patchy distribution of NOS in lower invertebrates can reflect uneven involvement of NO in neuronal NO signaling. The role of NO in chemosensory processing and feeding seems to be one of the first neuronal functions for NO in primitive animals. Feeding and chemosensory mechanisms are complimentary components of the same functional system, where the detection of the potential food stimuli is coupled to the appropriate feeding response.
One might also ask why NO would be associated with chemosensory and feeding mechanisms, and how they might be traced to the non-neuronal functions of NO in primitive eukaryotes? A reasonable explanation could be that neuronal signaling based on NO was developed from the role of NO in non-immune defense mechanisms. Indeed, the detection and consumption of food by any animal species involves the risk of exposure, both to potentially damaging stimuli, and to potential bacterial or viral infections; in other words feeding and chemosensory structures can be considered as primary openings for pathogen invasion. At the dawn of metazoan evolution, various microorganisms were the only sources of food for primitive animals. Therefore, acting as a universal bacteriostatic and cytotoxic molecule, NO is, indeed, a good candidate to have been incorporated into the feeding system. The formation of a protective barrier based on this toxic gas would also have helped to limit the bacterial assimilation of food, as well as preventing potential infection associated with long-term digestion. If this proposed evolutionary scenario is correct, it implies that inducible-like NOS with a higher yield of NO could indeed be a good candidate for the basal prototype of NOSs, and food stimuli would be potential inducers of NOS expression in this system; furthermore, similar enzymes can be found in chemosensory/feeding structures of some extant invertebrate species and overall NO production in these areas should be higher than in central neuronal structures.
Non-enzymatic NO synthesis is a complimentary and crucial component of the digestion process. In a highly acidic microenvironment, endogenous nitrites, together with nitrate and nitrite contamination from the food, serve as important sources of enzyme-independent NO formation. Furthermore, under certain conditions in the digestive tract, the requirement for NO can be fulfilled without NOS by the combined chemical synthesis of NO from nitrites and the reduction of nitrates/nitrites by heme-containing proteins or by symbiotic denitrifying prokaryotes.
During evolution, the initial cytotoxic role of NO caused by relatively high steady-state concentrations could be transformed first into the control of selective feeding responses, and then into the regulation of neuronal signaling in sensory and effector systems. For example, in the gastrointestinal tract, NO is involved in the control of smooth muscle motility and peristaltic movements. Envelopment of the gut by coelomic spaces (or with more specialized transport systems) would create the background for the origin of NO signaling between the digestive, excretory, and circulatory systems of higher invertebrates and vertebrate animals.
Alternatively, a role for NO in such neuronal functions as synaptogenesis (Ogilvie et al. 1995), growth cone motility (e.g., Hess et al., 1993; Renteria and Constantine-Paton, 1996; van Wagenen and Rehder, 1999), and neurodevelopment (e.g., Peunova and Enikolopov, 1995; Lin and Leise, 1996; Truman et al., 1996; Cramer et al., 1998; Gibbs and Truman, 1998; Wildemann and Bicker, 1999), as well as the NO-mediated apoptosis and inhibition of neuronal respiration, could be linked to the ancestral non-specific defense mechanisms, well conserved during the evolution of nervous systems.
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FUTURE DIRECTIONS |
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SYNOPSISGASES AS SIGNAL MOLECULESMULTIPLICITY OF NO SYNTHETIC...POTENTIAL NO-MEDIATED SIGNALING...NO SIGNALING IN LOWER...NO SIGNALING IN PLANTSTHE DISTRIBUTION AND FUNCTIONS...FUTURE DIRECTIONSReferences |
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At present, the comparative physiology of NO signaling is in its initial phase, providing a very first and quite superficial overview toward our understanding of its basic design, mechanisms and evolution. The hypothetical trends in the evolution of NO signaling outlined in the last chapter are still highly speculative, but I believe that several testable hypotheses can be generated to prove or disprove the proposed ideas. In any case, the first and the most important phyla to be analyzed in the nearest future are sponges, cnidarians, basal deuterostomata (including echinoderms and hemichordata) and lower chordata (e.g., cephalochordata, and tunicates, especially ascidian larvae). Cloning, molecular and functional characterization of NOS (or related enzymes) from these invertebrate models and, most importantly, from representatives of non-metazoan taxa (such as protozoa, fungi and plants), will lead to a major breakthrough in this endeavor. Developmental and sensory pathways would be the most crucial targets to allow us to follow the role of NO signaling from both comparative and evolutionary perspectives. Significant discoveries can also be expected as we analyze alternative NOS-independent pathways, the role of NO in ecological adaptations, and the contribution of NO to symbiotic interactions.
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ACKNOWLEDGMENTS |
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The author thanks James Netherton for his critical reading of the text, and his numerous comments and suggestions. This work was supported in part by Howard Hughes Medical Institute (#75195-540101; HHMI), NIH R01-NS39103 and NIH R01 MH60261 grants.
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FOOTNOTES |
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1 From the Symposium Nitric Oxide in the Invertebrates: Comparative Physiology and Diverse Functions presented at the Annual Meeting of the Society for Integrative and Comparative Biology, 4–8 January 2000, at Atlanta, Georgia.
2 E-mail: moroz{at}whitney.ufl.edu
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