Browsing by Author "De Waard, Michel"
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- ItemOpen AccessElectrophysiological characterization of a Cav3.2 calcium channel missense variant associated with epilepsy and hearing loss(2023-09-21) Stringer, Robin N.; Cmarko, Leos; Zamponi, Gerald W.; De Waard, Michel; Weiss, NorbertAbstract T-type calcium channelopathies encompass a group of human disorders either caused or exacerbated by mutations in the genes encoding different T-type calcium channels. Recently, a new heterozygous missense mutation in the CACNA1H gene that encodes the Cav3.2 T-type calcium channel was reported in a patient presenting with epilepsy and hearing loss—apparently the first CACNA1H mutation to be associated with a sensorineural hearing condition. This mutation leads to the substitution of an arginine at position 132 with a histidine (R132H) in the proximal extracellular end of the second transmembrane helix of Cav3.2. In this study, we report the electrophysiological characterization of this new variant using whole-cell patch clamp recordings in tsA-201 cells. Our data reveal minor gating alterations of the channel evidenced by a mild increase of the T-type current density and slower recovery from inactivation, as well as an enhanced sensitivity of the channel to external pH change. To what extend these biophysical changes and pH sensitivity alterations induced by the R132H mutation contribute to the observed pathogenicity remains an open question that will necessitate the analysis of additional CACNA1H variants associated with the same pathologies.
- ItemOpen AccessHow do T-type calcium channels control low-threshold exocytosis?(Landes Bioscience, 2012-03-12) Weiss, Norbert; De Waard, Michel; Zamponi, Gerald W.Low-voltage-activated T-type calcium channels act as a major pathway for calcium entry near the resting membrane potential in a wide range of neuronal cell types. Several reports have uncovered an unrecognized feature of T-type channels in the control of vesicular neurotransmitter and hormone release, a process so far thought to be mediated exclusively by high-voltage-activated calcium channels. However, the underlying molecular mechanisms linking T-type calcium channels to vesicular exocytosis have remained enigmatic. In a recent study, we have reported that Ca(v)3.2 T-type channel forms a signaling complex with the neuronal Q-SNARE syntaxin-1A and SNAP-25. This interaction that relies on specific Ca(v)3.2 molecular determinants, not only modulates T-type channel activity, but was also found essential to support low-threshold exocytosis upon Ca(v)3.2 channel expression in MPC 9/3L-AH chromaffin cells. Overall, we have indentified an unrecognized regulation pathway of T-type calcium channels by SNARE proteins, and proposed the first molecular mechanism by which T-type channels could mediate low-threshold exocytosis.