Proton Paths of Cardiac Immune Reflex

Functional protons contribute to proton-coupled electron transfer (PCET) in cellular biochemistry. PCET may be pH dependent or independent, and its capacities in converting substrate pH values are of particular interests to homeostasis, pharmacokinetics, pathogen, and etc. [1]. Voltage-gated proton channels (Hv ) exist widely from microorganisms to animal physiology with cell membranes, modulated by pH with strong temperature dependence and change pH in turn with depolarization [2]. Structural features exist in the ion channel pathways such as tetrameric voltage-gated K+, Na+, and Ca2+ helix ion channels, subsequently inducing intracellular and transmembrane flows through gating and cation depolarization [2,3]. It is not yet clear how positrons react to the anions with transient ion pairs with the depolarizing pulse in the open and gating momenta of PCET, but the gating pore may provide further insights into the inner structures of the process [3]. From pentameric ligand-gated ion channel (pLGIC), the Gloeobacter violaceus (GLIC) detection precision went from 5-10Å to 2-3Å on proton-gating process study, indicating that axial charges open the proton receptor with a nonconductive ion channel, break the inter facial hydrogen-bond network, and form a secondary electrostatic triad with hydrophobic residues before the gating process with proton-elicited channel currents during couple-binding [1,4]. Hydroxyl anions act both as the proton-receptor and transmembrane medium in the process, and the protonic motive force equation for adenosine triphosphatase (ATP) synthesis was theorized as [5]:

The evidence suggests the homeostasis of biochemical electrostasis and hydrostasis is interconnected by PCET, and regulates oxidization in the transmembrane domain [6,7].

It is well-experimented with wildtype zebrafish embryos for the inference that maternal proton homeostasis affects, through signaling, mammal and human fertilized eggs’ cell proliferation and prenatal developments [8-10]. The apoptotic experiments negatively indicated to the cardiac, immunological, and neurological development correlates between maternal and embryonic PCET [9,10]. With the gravitational differences in fetal position on geostationary terms, maternal umbilical cord changes the [de]polarization circuits in prevented apoptosis in prenatal development [11-13]. Apart from exterior sources from digestive metabolism such as glycolysis in the cytoplasm and secondary transmembrane protons, de novo proton-generation comes from ATP production in mitochondria [14]. In turn, cardiac mitochondria regulates and energizes ATP levels, with mitoflashes correlated to proton motive force (PMF) in mitochondrial reactive oxygen species (ROS) production, during which heat is generated by electron transport chain (ETC) [15,16]. Substrate oxidization consequently influences cardiac rhythms. ETC and ROS are influenced by multiple factors between the primary and secondary proton productions, with the involvement of T cells, submitochondrial particles, and transmembrane domain [16,17]. The plausibilities that cytochrome oxidase also contain a proton pump put ethnic differences in the ATP-driven proton injection and pumping cycles by exponential ratios in the reactive oxidization processes [17-19].

The hydrophilic proton transfer paths separate the protein motifs between proton extruders and proton sensors with Hv[14,20,21]. Electrochemical proton gradient in the transmembrane domain, typically generated by the vacuolar-type ATP (V-ATPase), energizes synaptic vesicles in neurons and in chromaffin granules in neuroendocrine chromaffin cells, accumulating neurotransmitters [22]. The V-ATPase V0 subunits to V1 receptor accumulation is pH dependent with Hv dynamics in the transmembrane domain, implying the involvement of PMF [2,21-23]. The at least 11 V-ATPase subunits’ organic and inorganic chemical potentials in receptor-dependent and acceptor-dependent biochemical and chemical reactions may shed new light in the interlinks in neurobiology, cellular biology, and biochemical materials [21,24,25]. The [de]polarization structural constraints in the V0-V1 complex phase correlates blood-borne physiological and pathological signaling with the immune reflexes and neuronal activities through exocytosis, extracellular nuclides, and the nerve terminals, guarded by the blood-brain barrier [11,22,26,27]. The fusogenic activities in the transmembrane domain can, therefore, influence respiratory, circulatory, neurological, and prenatal activities with the biochemical chain reactions.

The literature review organized the proton functions in the transmembrane interlink from ATP. PCET involved in the cardiac activities through ion channels correlate respiratory, circulatory, neuronal, and prenatal activities. Proton-gating with receptor and acceptor activities in the transmembrane domain influences biochemical oxidization during physiological depolarization and repolarization in the ATP synthesis cycles through hydrostaisis and hydro-equilibrium. Electrochemical gradient of proton activities in V-ATPase is the major conjunction in physiological PCET with immune reflex. The probabilities of biochemical exocytosis and apoptosis depend on the electrochemical force generated from PCET, and put enzymes into focus for further studies. Cardiac activities are tightly related to immune activities and immune reflex by ATP. Further research into the prenatal proton activities’ influence on neurological developments with the development of umbilical cord may open new doors for consciousness research.

None.

Yang I Pachankis is developing treatment solutions for SARSCoV- 2 and discussing investments with potential stakeholders.

1. David RW, Christopher JG, Jonathan F H, Christine FM, Caleb AK, et al. (2007) Proton-Coupled Electron Transfer. Chem Rev Nov 107(11): 5004-5064.
2. Thomas ED (2013) Voltage-Gated Proton Channels: Molecular Biology, Physiology, and Pathophysiology of the H_V Physiol Rev Apr 93(2): 599-652.
3. Rolando G (2020) The common features of tetrameric ion channels and the role of electrostatic interactions. Electrochem Commun Dec 121: 106866.
4. Haidai H, Kenichi A, Anaïs M, Zaineb F, Ludovic S, et al. (2018) Electrostatics, proton sensor, and networks governing the gating transition in GLIC, a proton-gated pentameric ion channel. Proc Natl Acad Sci USA 115(52): E12172-E12181.
5. James WL (2019) Electrostatically localized proton bioenergetics: better understanding membrane potential. Heliyon 5(7): e01961.
6. Ville RIK, Mårten W, Gerhard H (2014) Electrostatics, hydration, and proton transfer dynamics in the membrane domain of respiratory complex I. Proc Natl Acad Sci USA 111(19): 6988-6993.
7. Andrei V P, Pankaz K S, Zhen TC, Arieh W (2008) Electrostatic basis for the unidirectionality of the primary proton transfer in cytochrome c oxidase. Proc Natl Acad Sci USA 105(22): 7726-7731.
8. Emília R S, Michael B, Stefan H, Katalin H, Leonhard K, et al. (2018) Radiobiological effects and proton RBE determined by wildtype zebrafish embryos. PLoS ONE 13(11): e0206879.
9. SZILVIA B, TÜNDE T, EMÍLIA R S, RÓBERT P, IMRE Z S, et al. (2020) Dose-dependent Changes After Proton and Photon Irradiation in a Zebrafish Model. Anticancer Res 40(11): 6123-6135.
10. Gaëlle S, Eva B, Sophie C, Guillaume B, Grégory D (2022) Ultrahigh-Dose-Rate Proton Irradiation Elicits Reduced Toxicity in Zebrafish Embryos. Adv Radiat Oncol 8(2): 101124.
11. Yuki T, Yasunobu A, Daisuke K, Masaaki M (2017) The Gateway Reflex, a Novel Neuro-Immune Interaction for the Regulation of Regional Vessels. Front Immunol 8: 1321.
12. Illa T, Gwénaëlle LG, Alice K, Nadia G, Marie-Cécile AG, et al. (2012) H-NMR-Based Metabolic Profiling of Maternal and Umbilical Cord Blood Indicates Altered Materno-Foetal Nutrient Exchange in Preterm Infants. PLoS One 7(1): e29947.
13. Gianluigi M, Giuseppe M, Andrea F, Massimiliano C, Massimo F, et al. (2016) Time related variations in stem cell harvesting of umbilical cord blood. Sci Rep 6: 21404.
14. Wei-Zheng Z, Tian-Le X (2012) Proton production, regulation and pathophysiological roles in the mammalian brain. Neurosci Bull 28(1): 1-13.
15. Xianhua W, Xing Z, Di W, Zhanglong H, Tingting H, et al. (2017) Mitochondrial flashes regulate ATP homeostasis in the heart. eLife 6: e23908.
16. Brandon JB, Adam JT, Andrea MA, Minsoo K, Andrew P W (2018) Use the protonmotive force: mitochondrial uncoupling and reactive oxygen species. J Mol Biol 430(21): 3873-3891.
17. M Catia S, Stuart JF, Douglas BK, Philip J (1978) The Protonmotive Force in Bovine Heart Submitochondrial Particles. Biochem. J 174: 237-256.
18. Ramu A, Daniel MZ (2017) Biophysical comparison of ATP-driven proton pumping mechanisms suggests a kinetic advantage for the rotary process depending on coupling ratio. PLoS One 12(3): e0173500.
19. Yeong-Renn C, Jay LZ (2014) Cardiac Mitochondria and Reactive Oxygen Species Generation. Circ Res 114(3): 524-537.
20. Divya K, Umesh K, Yingying Z, MR Gunner (2021) Protein Motifs for Proton Transfers That Build the Transmembrane Proton Gradient. Front Chem 9: 660954.
21. Nathan N, Natalie P, Adiel C, Keren H, Vered P, et al. (2000) The Cellular Biology of Proton-motive Force Generation by V-ATPases. J Exp Biol 203(1): 89-95.
22. Sandrine PG, Mohamed RA, Marie E, Muriel A, Alexandre WM, et al. (2013) The V-ATPase membrane domain is a sensor of granular pH that controls the exocytotic machinery J Cell Biol 203(2): 283-298.
23. Dong W P, Robin H (2013) The vesicular ATPase: A missing link between acidification and exocytosis. J. Cell Biol 203(2): 171-173.
24. Dong L, Jie S, Panchao Y, Silas S, Andrew JB, et al. (2011) Inorganic–Organic Hybrid Vesicles with Counterion- and pH-Controlled Fluorescent Properties. J Am Chem Soc 133(35): 14010-14016.
25. Samantha B, Robert L B, Alex K S, Bailey D L, Bailey A B, et al. (2018) Amide Proton Transfer CEST of the Cervical Spinal Cord in Multiple Sclerosis Patients at 3T. Magn Reson Med 79(2): 806-814.
26. Alexander W L, Marie B, Brant E I (2012) Mechanisms of ATP release and signalling in the blood vessel wall. Cardiovasc Res 95(3): 269-280.
27. Ulf A, Kevin J T, (2012) Reflex Principles of Immunological Homeostasis. Annu Rev Immunol 30: 313-335.