Modulation of neuronal function by intracellular pH

Takahashi, Kyoh-Ichi; Copenhagen, David R.

doi:10.1016/0168-0102(95)00989-2

Cited by 60 publications

(42 citation statements)

References 27 publications

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“…Besides effects on cellular survival (45) or modulation of virtually all enzymatic activities, more specific effects may be exerted in the TRPV1-expressing free nerve endings, including a modulation of the conversion of the generator potential to action potentials or their further propagation along the axon. In line with this assumption, lowering the intracellular pH has been demonstrated to suppress the activity of high threshold voltage-gated Ca 2ϩ channels in sensory DRG neurons (46,47) as well as in other neuronal systems (48,49). Moreover, we could demonstrate that intracellular acidification modulates TRPV1 activity by inducing a voltage-dependent block taking effect mainly at potentials higher than Ϫ30 mV.…”

Section: Capsaicin-induced Changes Of the Ph I In Rat Dorsal Rootsupporting

confidence: 65%

TRPV1 Acts as Proton Channel to Induce Acidification in Nociceptive Neurons

Hellwig

Plant

Janson

et al. 2004

Journal of Biological Chemistry

141

101

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The low extracellular pH of inflamed or ischemic tissues enhances painful sensations by sensitizing and activating the vanilloid receptor 1 (TRPV1). We report here that activation of TRPV1 results in a marked intracellular acidification in nociceptive dorsal root ganglion neurons and in a heterologous expression system. A characterization of the underlying mechanisms revealed a Ca 2؉ -dependent intracellular acidification operating at neutral pH and an additional as yet unrecognized direct proton conductance through the poorly selective TRPV1 pore operating in acidic extracellular media. Large organic cations permeate through the activated TRPV1 pore even in the presence of physiological concentrations of Na ؉ , Mg 2؉ , and Ca 2؉ . The wide pore and the unexpectedly high proton permeability of TRPV1 point to a proton hopping permeation mechanism along the water-filled channel pore. In acidic media, the high relative proton permeability through TRPV1 defines a novel proton entry mechanism in nociceptive neurons.During ischemia or inflammation, pain sensation is augmented by the acidic extracellular pH (pH ext ). 1 A␦-and C-fiber neurons sense extracellular acid by means of two different classes of cation channels, namely TRPV1, the founding member of the vanilloid receptor-like transient receptor potential channel family (1, 2), and the acid-sensing ion channels (ASIC) (3, 4). Both channel types are expressed in small diameter dorsal root ganglion (DRG) neurons, and their role in mediating inflammatory hyperalgesia has been proven by gene deletion techniques (5-7). TRPV1, a poorly selective cation channel, integrates multiple pain-inducing stimuli, including noxious heat, vanilloids, and acidic extracellular pH (1, 8 -10). Inflammatory mediators such as bradykinin, serotonin, histamine, or prostaglandins further stimulate TRPV1 activity either by protein kinase C-dependent signals (11-13), by a release from a phosphatidylinositol 4,5-bisphosphate-dependent inhibition (14,15), by formation of 12-lipoxygenase products (16), or by a protein kinase A-mediated recovery from inactivation (17). Furthermore, extracellular acidification shifts the activation of TRPV1 toward lower temperature or ligand thresholds by protonation of an amino acid located in the vicinity of the pore loop (18). Although the role of the external pH ext in modulating TRPV1 activity is well established, a possible impact of TRPV1 activation on the intracellular pH has not been studied.A Ca 2ϩ influx component through activated voltage-or ligand-gated cation channels has been recognized to lower the intracellular pH (pH i ) in neurons or in neuroendocrine cells (19,20). We therefore asked the question whether activation of the Ca 2ϩ -permeable TRPV1 may also mediate intracellular acidification in native rat dorsal root ganglion neurons or in a heterologous expression system. Our results provide evidence for two independent TRPV1-mediated acidification signals, including an as yet unrecognized direct proton conductance through the activated TRPV1 p...

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Section: Capsaicin-induced Changes Of the Ph I In Rat Dorsal Rootsupporting

confidence: 65%

TRPV1 Acts as Proton Channel to Induce Acidification in Nociceptive Neurons

Hellwig

Plant

Janson

et al. 2004

Journal of Biological Chemistry

141

101

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“…The cellular metabolic state and pH i are intimately and reciprocally linked, and H + may be viewed as a metabolic intracellular messenger 36,37 . Accordingly, the H + and Ca 2+ sensitivity of the Slo1 BK channel conferred by His365, His394 and Asp367 is likely to have physiological implications.…”

Section: Discussionmentioning

confidence: 99%

Reciprocal regulation of the Ca2+ and H+ sensitivity in the SLO1 BK channel conferred by the RCK1 domain

Hou

Heinemann

et al. 2008

Nat Struct Mol Biol

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Increasing evidence suggests that intracellular H + directly stimulates large-conductance Ca 2+ -and voltage-activated K + (Slo1 BK) channels, thus providing a crucial link between membrane excitability and cell metabolism. Here we report that two histidine residues, His365 and His394, located in the intracellular RCK1 domain serve as the H + sensors of the Slo1 BK channel. Activation of the channel by H + requires electrostatic interactions between the histidine residues and a nearby negatively charged residue involved in the channel's high-affinity Ca 2+ sensitivity. Reciprocally, His365 and His394 also participate in the Ca 2+ -dependent activation of the channel, functioning as Ca 2+ mimetics once protonated. Therefore, a common motif in the RCK1 domain mediates the stimulatory effects of both H + and Ca 2+ , and provides a basis for the bidirectional coupling of cell metabolism and membrane electrical excitability.Normal functions of excitable cells, such as neurons and muscle cells, critically depend on an intimate and finely tuned regulation of membrane excitability by the cellular metabolic state. The metabolism, in turn, is reciprocally influenced by homeostasis of intracellular ions, and dysregulation of the ion concentrations accompanies many forms of abnormal excitability such as excitoxicity following ischemia/hypoxia 1 and also in neurodegenerative diseases 2 . Among the intracellular ion species, Ca 2+ and H + are particularly important, functioning in an intertwined manner; H + can interfere with numerous Ca 2+ -dependent processes and alters the intracellular Ca 2+ concentration ([Ca 2+ ] i ) [3][4][5] in turn, alterations in [Ca 2+ ] i modulate the intracellular H + homeostasis 6 .One of the key coupling mechanisms between the cellular metabolism and electrical excitability is the Slo1 (also known as KCNMA1) BK channel 7, 8. The two distinguishing features of the channel, large conductance and synergic activation by membrane depolarization and intracellular Ca 2+ , allow the channel to exert a negative feedback influence on cellular excitability under many physiological conditions, especially in neurons and muscle cells 9 . Consistent with this functional role, opening of BK channels often plays a cell-protective role against excitoxicity following hypoxia/ischemic insults 10,11 .As in other voltage-gated K + channels, four pore-forming Slo1 subunits form a functional BK channel complex, frequently with up to four auxiliary β subunits in a tissue-specific manner 12 . The transmembrane segments with its N-terminus facing the extracellular side contain the * To whom correspondence should be addressed. E-mail: hoshi@hoshi.org. Intracellular H + is also a potent modulator of BK channel function [22][23][24] . While some conflicting reports exist whether native BK channels are stimulated or inhibited by a decrease in intracellular pH (pH i ), recent evidence shows that, unlike most other K + channels, Slo1 BK channels measured under defined conditions are robustly activated by a decrease ...

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“…In other systems such as the somatic musculature of Ascaris lumbricoides (Demello and Maldonado, 1985), GABA also causes gap-junction uncoupling. This effect on dye coupling could be enacted through lowered intracellular pH by GABA action at GAB AA receptors (Takahashi and Copenhagen, 1996), as lowered pH decreases gap-junction permeability (Ueda et al, 1994).…”

Section: Dye Coupling (Figures 1 To 3)mentioning

confidence: 99%

Neuropeptides Exert Direct Effects on Rat Thymic Epithelial Cells in Culture

Head

Mentlein

Patay

et al. 1998

Journal of Immunology Research

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To determine if major thymic neuropeptides and neurotransmitters can directly influence the functional activity of cultured rat thymic epithelium, neuropeptides and neurotransmitters were applied, and intercellular communication, proliferation, and thymulin secretion assessed. After injections of a mixture of lucifer yellow dextran (too large to pass gap junctions) and cascade blue (which does) into single cells, some neuropeptides decrease dye coupling: 0.1 mM GABA (P < 0.0001), 100 nM NPY (P < 0.0001), 100 nM VIP (P < 0.001), 100 nM CGRP (P < 0.001), 100 nM SP (P < 0.01), and 0.1 mM histamine (P < 0.01), whereas 0.1 mM 5-HT, mM acetylcholine, and /xM isoproterenol (/3-adrenergic agonist) had no effect. Proliferation (incorporation of tritiated thymidine) was increased by CGRP (P 0.004) and histamine (P < 0.02), but decreased by isoproterenol (P 0.002), 5-HT (P 0.003), and acetylcholine (P < 0.05). The percentage of multinucleate cells was decreased after isoproterenol (2.5%), and increased after 5-HT (21.3%), GABA (15%), and histamine (15.1%). Compared to controls, thymulin in the supernatant was decreased after challenge with acetylcholine (52%), isoproterenol (71%), 5-HT (73%), and histamine (84%). This study demonstrates direct effects of neuropeptides and neurotransmitters on functional aspects of cultured thymic epithelial cells.

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Modulation of neuronal function by intracellular pH

Cited by 60 publications

References 27 publications

TRPV1 Acts as Proton Channel to Induce Acidification in Nociceptive Neurons

TRPV1 Acts as Proton Channel to Induce Acidification in Nociceptive Neurons

Reciprocal regulation of the Ca2+ and H+ sensitivity in the SLO1 BK channel conferred by the RCK1 domain

Neuropeptides Exert Direct Effects on Rat Thymic Epithelial Cells in Culture

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