Two sets of amino acids of the domain I of Cav2.3 Ca2+ channels contribute to their high sensitivity to extracellular protons

Abstract

Extracellular acidification decreases Ca(2+) current amplitude and produces a depolarizing shift in the activation potential (Va) of voltage-gated Ca(2+) channels (VGCC). These effects are common to all VGCC, but differences exist between Ca(2+) channel types and the underlying molecular mechanisms remain largely unknown. We report here that the changes in current amplitude induced by extracellular acidification or alkalinisation are more important for Cav2.3 R type than for Cav2.1 P/Q-type Ca(2+) channels. This difference results from a higher shift of Va combined with a modification of channel conductance. Although involved in the sensitivity of channel conductance to extracellular protons, neither the EEEE locus nor the divalent cation selectivity locus could explain the specificity of the pH effects. We show that this specificity involves two separate sets of amino acids within domain I of the Cavα subunit. Residues of the voltage sensor domain and residues in the pore domain mediate the effects of extracellular protons on Va and on channel conductance, respectively. These new insights are important for elucidating the molecular mechanisms that control VGCC gating and conductance and for understanding the role of extracellular protons in other channels or membrane-tethered enzymes with similar pore and/or voltage sensor domains.

Clustered Ca2+ Channels Are Blocked by Synaptic Vesicle Proton Release at Mammalian Auditory Ribbon Synapses

“…It displays no I Ca TB, although the P-type Ca 2+ channels are organized in nanodomains near the release sites (Nakamura et al, 2015). What is the reason for the absence of I Ca TB given that H + release has recently been observed at the calyx of Held (González-Inchauspe et al, 2017) and P-type Ca 2+ channels are highly sensitive to extracellular H+ (Cens et al, 2011)? One possible explanation comes from the spatial organization of the Ca 2+ channels at these active zones.…”

Modulation of synaptic depression of the calyx of Held synapse by GABAB receptors and spontaneous activity

“…Its inhibitory effect on voltage‐dependent Ca channels (Tombaugh & Somjen, 1996) could account for the strong effects on release. Release in the young‐adult calyx of Held is entirely controlled by Cav2.1 (P/Q) channels (Iwasaki et al 2000), which show both lower conductance and a positive shift in activation at low pH (Cens et al 2011). The other control we used was to apply a solution containing the calcium buffer EGTA.…”

Two central pattern generators from the crab, Cancer borealis, respond robustly and differentially to extreme extracellular pH

“…Given that the physiological properties of ion channels are sensitive to pH (Anwar et al, 322 2017;Bayliss et al, 2015;Catterall, 2000;Cens et al, 2011;Cook et al, 1984;Doering 323 and McRory, 2007;Guarina et al, 2017;Harms et al, 2017;Hille, 1968;Mahapatra et 324 al., 2011;Marcanoti et al, 2010;Tombaugh and Somjen, 1996;Vilin et al, 2012;Zhou et 325 al., 2018), one might imagine that a neuronal circuit might be as sensitive to changes in 326 pH as its most sensitive ion channels. Therefore, it is surprising that both the pyloric 327 rhythm of the STG and the cardiac ganglion rhythm in the crab, C. borealis, are 328 relatively insensitive to acute pH change from about pH 6.1 to pH 8.8 while the 329 individual functions of many ion channels are known to be considerably altered within 330 this pH range.…”