Elementary mechanisms producing facilitation of Cav2.1 (P/Q-type) channels

Dipayan Chaudhuri, John B. Issa, David T. Yue

Research output: Contribution to journalArticle

Abstract

The regulation of CaV2.1 (P/Q-type) channels by calmodulin (CaM) showcases the powerful Ca2+ decoding capabilities of CaM in complex with the family of CaV1-2 Ca2+ channels. Throughout this family, CaM does not simply exert a binary on/off regulatory effect; rather, Ca2+ binding to either the C- or N-terminal lobe of CaM alone can selectively trigger a distinct form of channel modulation. Additionally, Ca 2+ binding to the C-terminal lobe triggers regulation that appears preferentially responsive to local Ca2+ influx through the channel to which CaM is attached (local Ca2+ preference), whereas Ca 2+ binding to the N-terminal lobe triggers modulation that favors activation via Ca2+ entry through channels at a distance (global Ca2+ preference). CaV2.1 channels fully exemplify these features; Ca2+ binding to the C-terminal lobe induces Ca 2+-dependent facilitation of opening (CDF), whereas the N-terminal lobe yields Ca2+-dependent inactivation of opening (CDI). In mitigation of these interesting indications, support for this local/global Ca2+ selectivity has been based upon indirect inferences from macroscopic recordings of numerous channels. Nagging uncertainty has also remained as to whether CDF represents a relief of basal inhibition of channel open probability (Po) in the presence of external Ca2+, or an actual enhancement of Po over a normal baseline seen with Ba 2+ as the charge carrier. To address these issues, we undertake the first extensive single-channel analysis of CaV2.1 channels with Ca2+ as charge carrier. A key outcome is that CDF persists at this level, while CDI is entirely lacking. This result directly upholds the local/global Ca2+ preference of the lobes of CaM, because only a local (but not global) Ca2+ signal is here present. Furthermore, direct single-channel determinations of Po and kinetic simulations demonstrate that CDF represents a genuine enhancement of open probability, without appreciable change of activation kinetics. This enhanced-opening mechanism suggests that the CDF evoked during action-potential trains would produce not only larger, but longer-lasting Ca2+ responses, an outcome with potential ramifications for short-term synaptic plasticity.

Original languageEnglish (US)
Pages (from-to)385-401
Number of pages17
JournalJournal of General Physiology
Volume129
Issue number5
DOIs
StatePublished - May 2007

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Calmodulin
Neuronal Plasticity
Action Potentials
Uncertainty
voltage-dependent calcium channel (P-Q type)

ASJC Scopus subject areas

  • Physiology

Cite this

Elementary mechanisms producing facilitation of Cav2.1 (P/Q-type) channels. / Chaudhuri, Dipayan; Issa, John B.; Yue, David T.

In: Journal of General Physiology, Vol. 129, No. 5, 05.2007, p. 385-401.

Research output: Contribution to journalArticle

Chaudhuri, Dipayan ; Issa, John B. ; Yue, David T. / Elementary mechanisms producing facilitation of Cav2.1 (P/Q-type) channels. In: Journal of General Physiology. 2007 ; Vol. 129, No. 5. pp. 385-401.
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