Gasocrine signaling hypotheses

In cell biology textbooks, the existing terms for different types of cell signaling are insufficient to specifically denote gas-gasoreceptor-based signaling between dioxygen-producing organisms and aerobic organisms. Although ‘environmental signaling’ or ‘gaseous allelochemical-based signaling’ can be potentially used to describe such signaling, I recently proposed a more specific term ‘gasocrine signaling’ that encompasses all the diverse gas-gasoreceptor-based signaling that occurs both within and between cells, organisms and non-biotic factors. Using thought experiments and considering our planet earth and its organisms as one single organism and cells respectively, I propose the three hypotheses of gasocrine signaling in cell biology: 1) All living organisms composed of one or more cells require gasocrine signaling to sense, communicate, survive and propagate. 2) Gasocrine signaling mediated via gasoreceptor proteins (or yet to be identified gas-sensing RNA) is the most essential cellular and inter-organismal signaling. 3) All cells and acellular entities arising from or replicating in pre-existing cells require gasocrine signaling. Studying gasocrine signaling may help reveal the general principles in cellular and organismal communication and the role of abiotic components in it.  

1. Gasocrine signaling

How organelles or cells or organisms sense its environment and communicate is a fundamental question in biology. Protein-based receptors for light, temperature, amino acids, nutritional factors and environmental chemicals has been experimentally identified in numerous model organisms [1]. But gases are not only synthesized by organisms but also by environmental non biotic objects or machines [2]. In addition to gas sensors that depend on the gases for its catalytic activity, the identity of several gasoreceptors (gas-sensing proteins) that directly interact and sense gas/gaseous solute per se has been identified [3,4]. For the sake of discussions in this manuscript, although numerous metalloproteins structure can be affected by reactive species of gases [3], only the proteins acting via a heme domain or any other domain or region to sense gaseous molecules or gasotransmitters in their molecule state, if their binding or lack of binding (of gaseous solute) can trigger a cellular signal or response are considered as gasoreceptors [5].

Oxygen (O₂) is one of major gases that can act as a signaling molecule which is not only sensed by oxygen sensors that require O₂ for its activity but also via gasoreceptors that directly interact with O₂ [6,4,7]. For instance, heme-based gasoreceptors such as Escherichia coli Direct Oxygen Sensor (DosP)-phosphodiesterase, Leishmania soluble adenylate cyclase (HemAc-Lm) and Caenorhabditis elegans soluble guanylate cyclase (GCY-35) can interact and sense O₂ per se and trigger cellular signaling events and even changes in behavior of the organisms  [8–10]. Although similar O₂ gasoreceptors are yet to be identified in plants and vertebrates, the question arises as to how to refer to such gas-mediated interorganismal signaling especially when teaching to students [4,11].

Should a general term such as environmental gaseous signaling of biotic origin be used, or should the definition of pheromones must be relaxed to includes O₂ as a pheromone for aerobic organisms? [7] Or should gas-mediated signaling must be only used for gases such as nitric oxide (NO) or carbon monoxide and when it related to O₂, one must teach only about reactive oxygen species as signaling molecules or about the O₂ sensors that do not act as gasoreceptors?[4,13,14] To distinguish between reactive species-mediated and gas-mediated signaling events, I have recently proposed the term “gasocrine signaling” to unify all cellular signaling events mediated by gasoreceptors and gaseous signaling molecules. A gasocrine signaling occurs when a gasotransmitter or gaseous signaling molecule can bind to a gasoreceptor (or sensor or chemoreceptor) in its molecular state and trigger a cellular signal or response [5,15]. It is also possible that gasocrine signaling may occur via yet-to-be identified gas-sensing nucleic acids (riboceptors or deoxyriboceptors) or potentially even other classes of biomolecules [15].

2. Diversity of gasoreceptors

Gasoreceptors seem to be highly diverse and the diversity arises from the gases it senses, the cellular localization of gasoreceptors, the number and variety in its signaling domains and the metal cofactors that interact with gases and even the possibility of metal cofactor-independent gas interaction-based “non-enzymatic” post translational modifications (Figure 1) [3,15].

Diversity in signaling domains: With respect to signaling domains, gasoreceptors seem to be enzymes, transcription factors and even ion-channels [16,17]. Till date, experimentally validated enzyme-based gasoreceptors include soluble guanylate cyclase, soluble adenylate cyclase, histidine kinases and phosphodiesterases [3,15]. Theoretically, as long as a proteins’ activity is affected by gas interaction, every gas-interacting protein irrespective of its function are putative gasoreceptors [18]. With regards to the need for molecular cascade for the proteins to be considered as a receptor, as long as molecular signaling events occurs in or between cytoplasm or organelle-like condensates, organelles or cells and triggers a response, whether we consider it as a “cascade” or not, for the cell or the condensate or the organelle, it is a “cascade” as it has triggered a response. The response does not have to be due to the message to the nucleus and its counter response. Responses could be even to other organelles or organelle-like elements in a cell.

For instance, what is the identity of the O₂-gasoreceptor in cells that lacks nuclei? As I recently proposed in a preprint, a debate is warranted if the gas-interacting proteins such as vertebrate hemoglobin can be considered as an O₂ gasoreceptor in a split-component signaling system or a protogasoreceptor in a proto-component signaling system [19]. Till date, vertebrate hemoglobin or paralogues of it are not referred as receptors for O₂  but rather as metabolic sensors [20]. If vertebrate hemoglobin has been well known as a major O₂ sensor or receptor, then why is it not mentioned so in some of the most recent reviews on O₂ sensing or prestigious awards related to it [4,6,21,22]. If hemoglobin is accepted as a gasoreceptor or protogasoreceptor for O₂, similar rationale must be also considered for all the other gas-interacting proteins and metalloproteins that can interact with gases.

Diversity of metal cofactors in gasoreceptors: To the best of my knowledge, majority of the gasoreceptors mediating gasocrine signaling seem to require metal ions or cofactors. Specifically, O₂-, NO-, CO- and ethylene-sensing gasoreceptors bind to gaseous solutes via heme- or copper ion-binding domain and signal via additional enzymatic or transcription factor domains [3,15]. But then the question arises, are heme- and copper ion-based metalloproteins are the only metalloproteins that act as gasoreceptors? Even non-heme, di-iron-based gasoreceptors exist [23]. This raises a question about all the other metalloproteins that can interact with gases?[24] In many organisms, cells also have transporters for various other metal ions such as zinc, molybdenum, nickel, selenium and so on [25,26]. It is unclear how many other different metalloproteins can interact with gases in vivo and act as gasoreceptors. Even zinc-based metalloproteins seem to be putative candidates for H₂S gasoreceptors and even inert gases such as argon (Ar) or dinitrogen (N₂) and gases such as methane may potentially have gasoreceptors as well  [27].

Finally, one must also not ignore the possibility of gasoreceptors that can interact with gases independent of metal cofactors. For instance, carbon dioxide (CO₂) can interact with proteins such as hemoglobin or ubiquitin. The interactions are based on reversible carbamylation of neutral N-terminal α-amino or lysine ε-amino groups [28–30]. But a debate is warranted if carbamylation or other non-enzymatic posttranslational modification-mediated gas-protein interactions can be also considered akin to ligand-interactions to receptors. Addressing this question and agreement for this question is important. For instance, instead of referring to vertebrate hemoglobin as a protogasoreceptor of O₂ in proto-component signaling system, it could be also referred to as CO₂ gasoreceptor in one-component signaling system, if CO₂-bound and O₂-unbound hemoglobin can synthesize NO [31,32].

3. Gasocrine hypotheses from the perspective of aerobic organisms

Gasocrine signaling not only encompasses gas-gasoreceptor signaling that occurs inside or between cells or organelles but also between two different organisms as well (Figure 2).  For the sake of discussion, I will first address aerobic organisms that require O₂ for its metabolism and survival. For O₂-based inter-organismal gasocrine signaling to occur, first, O₂ must be synthesized and diffuse out of O₂-producing organisms.  Similar to an experiment that involve knocking out the ligand-coding gene/s, if we knockout all the genes encoding O₂-synthesis in all the O₂-generating organisms in our planet earth, it will likely lead to cessation of O₂-dependent aerobic life but not necessarily all the biotic life in the planet earth. So O₂ is a signaling molecule and message at physiological concentrations for aerobic organisms is simply live irrespective of the biochemical means living is achieved.

Nevertheless, a strong argument to rule out O₂ as a signaling molecule is the fact that the role of O₂ is primarily in metabolism or as terminal electron acceptor in the mitochondrial electron transport chain [33,34]. But if we consider hemoglobin or its paralogues as one of the primary protogasoreceptor or gasoreceptor for O₂, then I would argue at least in vertebrates, why only look at the role of O₂ in mitochondria? Why are we ignoring the fact that hemoglobin-based O₂-mediated gasocrine signaling or perhaps the lack of the signaling under O₂-bound state is equally important for the cell or the organism [19,35].  One must also not ignore the fact that hemoglobin subunits can also be localized in mitochondria and can also potentially act as a protogasoreceptor or gasoreceptor [36,37]. Moreover, in the absence of O₂, some of the mitochondrial electron transport chain subunits also act as protogasoreceptors for gases that can competitively inhibit its activity. For instance, NO, H₂S or even hydrogen cyanide (HCN) can competitively inhibit cytochrome c oxidase (Complex IV) blocking its ability to reduce oxygen to water [38–41]. Is water a signaling molecule and will the lack of it inside a cell or mitochondria will be recognized? Apart from its role as a solvent, I had earlier argued that water per se is a signaling molecule and also proposed that some gasoreceptors may have a dual role as aquareceptors [42–44]. Thus cytochrome c oxidase can be considered as one of the protogasoreceptors for NO mediating gasocrine signaling. So the absence of O₂ in aerobic organism or cells will still lead to gasocrine signaling based on other gases or the fact that water-based signaling events will be disrupted. Overall, this further highlights the interconnectedness of gasocrine signaling events from O₂-producing organisms to organelles such as mitochondria in aerobic organisms.

Currently, we do not know the identity of all the O₂-sensing gasoreceptors in various cell types. If there are any O₂-binding proteins in a cell, O₂-based gasocrine signaling likely occurs in such cell that generates, receives and sense O₂ per se based on gasoreceptors in one- or two- or multi- or split- or proto-component signaling systems. Based on the above arguments, I propose that any aerobic organism will require O₂-based gasocrine signaling for communication, survival, and asexual or sexual reproduction.

As inter-organismal O₂-based gasocrine signaling is essential for aerobic life, gasocrine signaling mediated via gasoreceptor proteins is one of the most essential cellular and inter-organismal signaling. Finally, as replication of viruses in aerobic organisms also requires cells under physiologically active conditions, I propose that all cellular entities arising from or replicating in pre-existing cells require gasocrine signaling as well [45].

4. Three postulates of the gasocrine hypotheses

Apart from O₂, as long as gasoreceptors and gasoriboceptors can be identified, the ‘ligands’ in gasocrine signaling includes all the biotically and abiotically generated gases that can trigger gasocrine signaling [46]. It is unclear how many different gases can an organelle or cell or organism produce besides the well-studied gases such as O₂, NO, CO, CO₂, C₂H₄, and H₂S? Recently, Reactive oxygen species (ROS)-based CH₄ production has been identified in several model organisms, and H₂ has also been identified as a signaling molecule in plants [47,48]. But the identity of CH₄- and H₂-sensing gasoreceptors in vertebrates or plants is still unknown [3,48]. Moreover, one needs to also debate if volatile organic compounds can be considered as “gaseous signaling molecules” that mediate gasocrine signaling [49].

Overall, gasocrine signaling encompasses not only gas-based inter-organismal signaling but also gas-based autocrine and paracrine signaling (Fig. 2). Hence, to completely disrupt gasocrine signaling in an organism, one must ensure that it cannot receive, produce or sense any gases. To the best of knowledge, currently, experiments to create and test organisms that cannot produce or sense none of the gases could be impossible to perform due to the limitation in the knowledge on the identity of all the generated gases, gasoreceptors, gasoriboceptors and gas synthesis pathways [3]. Based on these arguments, I propose the following postulates: All living organisms composed of one or more cells require gasocrine signaling to sense, communicate, survive and propagate. Gasocrine signaling mediated via gasoreceptor proteins (or yet to be identified gas-sensing riboceptors) is the most essential cellular and inter-organismal signaling. All cells and acellular entities arising from or replicating in pre-existing cells require gasocrine signaling.

5. Conclusion

The immediate implications of these postulates is that it supplements cell theory [50]. However the unintended implications is the perceivable challenge to the four pillars of biology: Evolution, Metabolism, Genetics, and Cell theory. However, my original intention was never to challenge these pillars or the mechanisms underlying it. I started with a simple question, if there is a receptor for nitric oxide, is there a receptor for oxygen. Discussions and debate among some of the leading experts led to more questions. Rather than perceiving it as a challenge to the four pillars of biology, perhaps understanding these pillars from a perspective of the pressure and challenges to it posed by gases and how gasoreceptors (and gas-sensing riboceptors) would have potentially mitigated those challenges is a more attractive alternative.

Figure 1 Types of gasoreceptors.

Figure 2 Types of gasocrine signaling.

(A) Autocrine-based gasocrine signaling. (B) Paracrine-based gasocrine signaling. (C) Endocrine-based gasocrine signaling. (D) Inter-organismal and non-biotic factor-based gasocrine signaling.

ABBREVIATIONS

O2       dioxygen

NO      Nitric oxide

CO      Carbon monoxide

CO₂     Carbon dioxide

ROS     Reactive oxygen species

AUTHOR CONTRIBUTIONS

Savani Anbalagan: conceptualization, writing of the original draft, and review and editing.

ACKNOWLEDGMENT

The author contributes this work to the late Robert Remak from Poznan, Poland. The author thank Zofia Szweykowska-Kulinska (Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland) for allowing him to attend her inspiring lectures on molecular evolution. The author also thank Agnieszka Chacinska (Past affiliation: Centre of New Technologies, University of Warsaw, Regenerative Mechanisms for Health - International Research Agendas Programme and current affiliation: International Institute of Molecular Machines and Mechanisms, Polish Academy of Science, Warsaw, Poland) for suggesting him to attend the 44th FEBS Congress meeting. The author also thank José López Barneo (University of Seville, Spain) & James Imlay (University of Illinois, Urbana-Champaign, USA) for active discussions on Oxygen sensing. The author apologizes to authors whose work has not been cited and lack of citation of such works is not due to personal biases.

FUNDING

S.A. is supported by National Science Centre grants (SONATA-BIS 2020/38/E/NZ3/00090 and SONATA 2021/43/D/NZ3/01798).

DISCLOSURE

The funding agency and institution S.A. is affiliated with was not involved in the contents of the manuscript.

CONFLICT OF INTEREST

None.

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