Importance of voltage-dependent inactivation in N-type calcium channel regulation by G-proteins.: Channel inactivation in G-protein regulation

Abstract : Direct regulation of N-type calcium channels by G-proteins is essential to control neuronal excitability and neurotransmitter release. Binding of the G(betagamma) dimer directly onto the channel is characterized by a marked current inhibition ("ON" effect), whereas the pore opening- and time-dependent dissociation of this complex from the channel produce a characteristic set of biophysical modifications ("OFF" effects). Although G-protein dissociation is linked to channel opening, the contribution of channel inactivation to G-protein regulation has been poorly studied. Here, the role of channel inactivation was assessed by examining time-dependent G-protein de-inhibition of Ca(v)2.2 channels in the presence of various inactivation-altering beta subunit constructs. G-protein activation was produced via mu-opioid receptor activation using the DAMGO agonist. Whereas the "ON" effect of G-protein regulation is independent of the type of beta subunit, the "OFF" effects were critically affected by channel inactivation. Channel inactivation acts as a synergistic factor to channel activation for the speed of G-protein dissociation. However, fast inactivating channels also reduce the temporal window of opportunity for G-protein dissociation, resulting in a reduced extent of current recovery, whereas slow inactivating channels undergo a far more complete recovery from inhibition. Taken together, these results provide novel insights on the role of channel inactivation in N-type channel regulation by G-proteins and contribute to the understanding of the physiological consequence of channel inactivation in the modulation of synaptic activity by G-protein coupled receptors.
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Article dans une revue
Pflügers Archiv European Journal of Physiology, Springer Verlag (Germany), 2007, 454 (1), pp.115-29. 〈10.1007/s00424-006-0184-0〉
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Norbert Weiss, Abir Tadmouri, Mohamad Mikati, Michel Ronjat, Michel De Waard. Importance of voltage-dependent inactivation in N-type calcium channel regulation by G-proteins.: Channel inactivation in G-protein regulation. Pflügers Archiv European Journal of Physiology, Springer Verlag (Germany), 2007, 454 (1), pp.115-29. 〈10.1007/s00424-006-0184-0〉. 〈inserm-00378043〉

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