Quinine, intracellular pH and modulation of hemi-gap junctions in catfish horizontal cells

Dixon, D.; Takahashi, Kyoh-Ichi; Bieda, Mark; Copenhagen, David R.

doi:10.1016/s0042-6989(96)00129-0

Cited by 29 publications

(22 citation statements)

References 27 publications

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“…Quinine evoked a con- centration-dependent release of ATP from C6 cells expressing connexin43, in a concentration range (50 -500 M) similar to that observed to activate connexin hemichannels (23)(24)(25). ATP concentrations measured 1 min following quinine exposure were 24, 28, and 33 M for 50, 100, and 500 mM quinine, respectively (n ϭ 8 each, p Ϫ0.012 by single factor analysis of variance).…”

Section: Low Casupporting

confidence: 59%

See 1 more Smart Citation

Intercellular Calcium Signaling in Astrocytes via ATP Release through Connexin Hemichannels

Stout¹,

Costantin²,

Naus³

et al. 2002

Journal of Biological Chemistry

797

720

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Section: Low Casupporting

confidence: 59%

“…Quinine has been reported to activate connexin hemichannels in multiple preparations (23)(24)(25). Quinine evoked a con- centration-dependent release of ATP from C6 cells expressing connexin43, in a concentration range (50 -500 M) similar to that observed to activate connexin hemichannels (23)(24)(25).…”

Section: Low Camentioning

confidence: 52%

Intercellular Calcium Signaling in Astrocytes via ATP Release through Connexin Hemichannels

Stout¹,

Costantin²,

Naus³

et al. 2002

Journal of Biological Chemistry

797

720

View full text Add to dashboard Cite

“…Previous studies indicated that quinine activated putative hemichannellike currents in horizontal cells of skate and perch retina (17)(18)(19) and potentiated gap junction hemichannel currents in oocytes expressing certain connexins (e.g., Cx35) and not others (e.g., Cx43) (20). We now demonstrate in mammalian cells that quinine blocks certain types of gap junction channels in a reversible and concentration-dependent manner, whereas gap junctions formed of other connexins are unaffected.…”

supporting

confidence: 54%

Quinine blocks specific gap junction channel subtypes

Srinivas

Hopperstad

Spray

2001

Proc. Natl. Acad. Sci. U.S.A.

194

165

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We demonstrate that the antimalarial drug quinine specifically reduces currents through gap junctions formed by some connexins (Cx) in transfected mammalian cells, but does not affect other gap junction types. Quinine blocked Cx36 and Cx50 junctional currents in a reversible and concentration-dependent manner with half maximal blocking concentrations of 32 and 73 M, respectively; Hill coefficients for block by quinine were about 2 for both connexins. In contrast, quinine did not substantially block gap junction channels formed by Cx26, Cx32, Cx40, and Cx43, and only moderately affected Cx45 junctions. To determine the location of the binding site of quinine (pKa ‫؍‬ 8.7), we investigated the effect of quinine at various external and internal pH values and the effect of a permanently charged quaternary derivative of quinine. Our results indicate that the binding site for quinine is intracellular, possibly within the pore. Single-channel studies indicated that exposure to quinine induced slow transitions between open and fully closed states that decreased open probability of the channel. Quinine thus offers a potentially useful method to block certain types of gap junction channels, including those between neurons that are formed by Cx36. Moreover, quinine derivatives that are excluded from other types of membrane channels may provide molecules with connexin-specific as well as connexin-selective blocking activity.

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“…Similar to previous reports for neurons (36,41,42), bath perfusion of 1 mM quinine increased intracellular pH, whereas NH 4 Cl withdrawal decreased intracellular pH in CHO cells (data not shown). To examine the possibility that modulation of ASICs by pH i depends on the presence of a specific ASIC subunit, we studied the effects of intracellular pH-modifying agents on the current mediated by different ASIC subunits expressed in CHO cells.…”

Section: Changing Intracellular Ph Alters Ogd-induced Injury Of Cultusupporting

confidence: 91%

Modulation of Acid-sensing Ion Channel 1a by Intracellular pH and Its Role in Ischemic Stroke

Leng

Feng

et al. 2016

Journal of Biological Chemistry

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An important contributor to brain ischemia is known to be extracellular acidosis, which activates acid-sensing ion channels (ASICs), a family of proton-gated sodium channels. Lines of evidence suggest that targeting ASICs may lead to novel therapeutic strategies for stroke. Investigations of the role of ASICs in ischemic brain injury have naturally focused on the role of extracellular pH in ASIC activation. By contrast, intracellular pH (pH i ) has received little attention. This is a significant gap in our understanding because the ASIC response to extracellular pH is modulated by pH i , and activation of ASICs by extracellular protons is paradoxically enhanced by intracellular alkalosis. Our previous studies show that acidosis-induced cell injury in in vitro models is attenuated by intracellular acidification. However, whether pH i affects ischemic brain injury in vivo is completely unknown. Furthermore, whereas ASICs in native neurons are composed of different subunits characterized by distinct electrophysiological/pharmacological properties, the subunit-dependent modulation of ASIC activity by pH i has not been investigated. Using a combination of in vitro and in vivo ischemic brain injury models, electrophysiological, biochemical, and molecular biological approaches, we show that the intracellular alkalizing agent quinine potentiates, whereas the intracellular acidifying agent propionate inhibits, oxygen-glucose deprivation-induced cell injury in vitro and brain ischemiainduced infarct volume in vivo. Moreover, we find that the potentiation of ASICs by quinine depends on the presence of the ASIC1a, ASIC2a subunits, but not ASIC1b, ASIC3 subunits. Furthermore, we have determined the amino acids in ASIC1a that are involved in the modulation of ASICs by pH i .A common feature of brain ischemia is acidosis (1-5), which plays a critical role in the ensuing brain injury. However, the mechanisms of acidosis-induced injury remain poorly understood. Acidosis activates acid-sensing ion channels (ASICs), 4 a family of proton-gated cation channels that belong to the degenerin and epithelial Na ϩ channel superfamily of ion channels (6). These channels are expressed in neurons throughout the peripheral and central nervous systems (6 -9). In sensory neurons, ASICs play important roles in nociception (9 -11), mechanosensation (12, 13), and taste transduction (14), whereas in the central nervous system (CNS), ASICs are involved in processes such as synaptic plasticity, learning, and memory (15-17). The specific ASIC important in acidosis-induced injury is the ASIC1a subtype (5, 18). This subtype has a higher sensitivity to protons and is both sodium-and calciumpermeable. Neuronal injury induced by ASIC activation is independent of glutamate receptor-mediated excitotoxicity (5, 18), offering provocative new evidence for ASICs as potential new targets for stroke therapy (4, 5, 19 -21).In the brain, energy is stored mainly in the form of the high energy phosphate compound ATP. In normoxia, ATP is predominantly produced by oxid...

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Quinine, intracellular pH and modulation of hemi-gap junctions in catfish horizontal cells

Cited by 29 publications

References 27 publications

Intercellular Calcium Signaling in Astrocytes via ATP Release through Connexin Hemichannels

Intercellular Calcium Signaling in Astrocytes via ATP Release through Connexin Hemichannels

Quinine blocks specific gap junction channel subtypes

Modulation of Acid-sensing Ion Channel 1a by Intracellular pH and Its Role in Ischemic Stroke

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