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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Weiss, N; Tadmouri, A; Mikati, M; Ronjat, M; De Waard, M

Published Date

  • April 2007

Published In

Volume / Issue

  • 454 / 1

Start / End Page

  • 115 - 129

PubMed ID

  • 17171365

Pubmed Central ID

  • 17171365

International Standard Serial Number (ISSN)

  • 0031-6768

Digital Object Identifier (DOI)

  • 10.1007/s00424-006-0184-0

Language

  • eng

Conference Location

  • Germany