Elementary mechanisms producing facilitation of Cav2.1 (P/Q-type) channels.
The regulation of Ca(V)2.1 (P/Q-type) channels by calmodulin (CaM) showcases the powerful Ca(2+) decoding capabilities of CaM in complex with the family of Ca(V)1-2 Ca(2+) channels. Throughout this family, CaM does not simply exert a binary on/off regulatory effect; rather, Ca(2+) 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 Ca(2+) influx through the channel to which CaM is attached (local Ca(2+) preference), whereas Ca(2+) binding to the N-terminal lobe triggers modulation that favors activation via Ca(2+) entry through channels at a distance (global Ca(2+) preference). Ca(V)2.1 channels fully exemplify these features; Ca(2+) binding to the C-terminal lobe induces Ca(2+)-dependent facilitation of opening (CDF), whereas the N-terminal lobe yields Ca(2+)-dependent inactivation of opening (CDI). In mitigation of these interesting indications, support for this local/global Ca(2+) 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 (P(o)) in the presence of external Ca(2+), or an actual enhancement of P(o) 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 Ca(V)2.1 channels with Ca(2+) 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 Ca(2+) preference of the lobes of CaM, because only a local (but not global) Ca(2+) signal is here present. Furthermore, direct single-channel determinations of P(o) 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 Ca(2+) responses, an outcome with potential ramifications for short-term synaptic plasticity.
Chaudhuri
Dipayan
D
Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. dyue@bme.jhu.edu
Issa
John B
JB
Yue
David T
DT
D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020864:Calcium Channels, N-Type / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling; D002147:Calmodulin / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D015640:Ion Channel Gating; D007700:Kinetics; D008564:Membrane Potentials; D008954:Models, Biological; D009473:Neuronal Plasticity; D018408:Patch-Clamp Techniques; D020033:Protein Isoforms / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D014162:Transfection
D002118:Calcium; D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D002147:Calmodulin; D020033:Protein Isoforms; C105656:CACNA1A protein, human; C425903:CACNA2D1 protein, human