Importance of voltage-dependent inactivation in N-type calcium channel regulation by G-proteins.
Résumé
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.
Fichier principal
Weiss_Eur_J_Physiol_Manuscript-revised.pdf (203.28 Ko)
Télécharger le fichier
Weiss_Fig.1.JPG (2.87 Mo)
Télécharger le fichier
Weiss_Fig.2.JPG (2.53 Mo)
Télécharger le fichier
Weiss_Fig.3.JPG (2.97 Mo)
Télécharger le fichier
Weiss_Fig.4.JPG (2.44 Mo)
Télécharger le fichier
Weiss_Fig.5.JPG (2.42 Mo)
Télécharger le fichier
Weiss_Fig.6.JPG (2.52 Mo)
Télécharger le fichier
Weiss_Fig.7.JPG (3.07 Mo)
Télécharger le fichier
Weiss_Fig.8.JPG (3.43 Mo)
Télécharger le fichier
inserm-00378043_edited.pdf (1.18 Mo)
Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)
Format : Autre
Format : Autre
Format : Autre
Format : Autre
Format : Autre
Format : Autre
Format : Autre
Format : Autre
Origine : Fichiers produits par l'(les) auteur(s)
Loading...