| Autor: |
Nilsson M; Division of Cell and Neurobiology, Department of Biomedical and Clinical Sciences, Linköping University, SE-581 85 Linköping, Sweden., Wang K; Division of Cell and Neurobiology, Department of Biomedical and Clinical Sciences, Linköping University, SE-581 85 Linköping, Sweden., Mínguez-Viñas T; Division of Cell and Neurobiology, Department of Biomedical and Clinical Sciences, Linköping University, SE-581 85 Linköping, Sweden., Angelini M; Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA., Berglund S; Division of Cell and Neurobiology, Department of Biomedical and Clinical Sciences, Linköping University, SE-581 85 Linköping, Sweden., Olcese R; Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.; Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA., Pantazis A; Division of Cell and Neurobiology, Department of Biomedical and Clinical Sciences, Linköping University, SE-581 85 Linköping, Sweden.; Wallenberg Center for Molecular Medicine, Linköping University, SE-581 85 Linköping, Sweden. |
| Abstrakt: |
How G proteins inhibit N-type, voltage-gated, calcium-selective channels (Ca V 2.2) during presynaptic inhibition is a decades-old question. G proteins Gβγ bind to intracellular Ca V 2.2 regions, but the inhibition is voltage dependent. Using the hybrid electrophysiological and optical approach voltage-clamp fluorometry, we show that Gβγ acts by selectively inhibiting a subset of the four different Ca V 2.2 voltage-sensor domains (VSDs I to IV). During regular "willing" gating, VSD-I and -IV activations resemble pore opening, VSD III activation is hyperpolarized, and VSD II appears unresponsive to depolarization. In the presence of Gβγ, Ca V 2.2 gating is "reluctant": pore opening and VSD I activation are strongly and proportionally inhibited, VSD IV is modestly inhibited, while VSD III is not. We propose that Gβγ inhibition of VSDs I and IV underlies reluctant Ca V 2.2 gating and subsequent presynaptic inhibition. |
