title: Importance of voltage-dependent inactivation in N-type calcium channel regulation by G-proteins.
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.
authors.affiliation: Laboratoire Canaux Calciques, Fonctions et Pathologies, INSERM U607, Commissariat à l'Energie Atomique, 17 rue des Martyrs, 38054 Grenoble Cedex 09, France.
authors.forename: Norbert
authors.initials: N
authors.lastname: Weiss
authors.forename: Abir
authors.initials: A
authors.lastname: Tadmouri
authors.forename: Mohamad
authors.initials: M
authors.lastname: Mikati
authors.forename: Michel
authors.initials: M
authors.lastname: Ronjat
authors.forename: Michel
authors.initials: M
authors.lastname: De Waard
mesh_terms: D000818:Animals; D020864:Calcium Channels, N-Type / Q000378:metabolism / Q000502:physiology*; D004553:Electric Conductivity; D004594:Electrophysiology; D019204:GTP-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D007700:Kinetics; D020033:Protein Isoforms / Q000378:metabolism / Q000502:physiology; D011817:Rabbits; D051381:Rats; D017450:Receptors, Opioid, mu / Q000502:physiology; D013997:Time Factors
chemical_list: D020864:Calcium Channels, N-Type; D020033:Protein Isoforms; D017450:Receptors, Opioid, mu; D019204:GTP-Binding Proteins