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The Journal of Neuroscience, May 1, 2001, 21(9):2939-2948
Distinct Molecular Determinants Govern Syntaxin 1A-Mediated
Inactivation and G-Protein Inhibition of N-Type Calcium Channels
Scott E.
Jarvis and
Gerald W.
Zamponi
Departments of Physiology and Biophysics and Pharmacology and
Therapeutics, Neuroscience and Smooth Muscle Research Groups,
University of Calgary, Calgary, T2N 4N1, Canada
We have reported recently that syntaxin 1A mediates two
effects on N-type channels transiently expressed in tsA-201 cells: a
hyperpolarizing shift in the steady-state inactivation curve as well as
a tonic inhibition of the channel by G-protein   subunits (Jarvis
et al., 2000). Here we have examined some of the molecular determinants
and factors that modulate the action of syntaxin 1A on N-type calcium
channels. With the additional coexpression of SNAP25, the syntaxin
1A-induced G-protein modulation of the channel became reduced in
magnitude by ~50% but nonetheless remained significantly higher than
the low levels of background inhibition seen with N-type channels
alone. In contrast, coexpression of nSec-1 did not reduce the syntaxin
1A-mediated G-protein inhibition; however, interestingly, nSec-1 was
able to induce tonic G-protein inhibition even in the absence of
syntaxin 1A. Both SNAP25 and nSec-1 blocked the negative shift in
half-inactivation potential that was induced by syntaxin 1A. Activation
of protein kinase C via phorbol esters or site-directed mutagenesis of
three putative PKC consensus sites in the syntaxin 1A binding region of
the channel (S802, S896, S898) to glutamic acid (to mimic a permanently
phosphorylated state) did not affect the syntaxin 1A-mediated G-protein
modulation of the channel. However, in the S896E and S898E mutants, or
after PKC-dependent phosphorylation of the wild-type channels, the
susceptibility of the channel to undergo shifts in half-inactivation
potential was removed. Thus, separate molecular determinants govern the ability of syntaxin 1A to affect N-type channel gating and its modulation by G-proteins.
Key words:
SNARE proteins; protein kinase C; G  ; phosphorylation; calcium
channels; site-directed mutagenesis
Copyright © 2001 Society for Neuroscience 0270-6474/01/2192939-10$05.00/0
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