Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 97, Issue 16, Pages 9293-9298Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.160589697
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N- and P/Q-type Ca2+ channels regulate a number of critical physiological processes including synaptic transmission and hormone secretion. These Ca2+ channels are multisubunit proteins, consisting of a pore-forming alpha(1), and accessory beta and alpha(2)delta subunits each encoded by multiple genes and splice variants. beta subunits alter current amplitude and kinetics, The beta(2a) subunit is associated with slowed inactivation, an effect that requires the palmitoylation of two N-terminal cysteine residues in beta(2a). In the current manuscript, we studied steady state inactivation properties of native N- and P/Q-type Ca2+ channels and recombinant N-type Ca2+ channels, When bovine alpha(1), and beta(2a) and human alpha(2)delta were coexpressed in tsA 201 cells, we observed significant variations in inactivation; some cells exhibited virtually no inactivation as the holding potential was altered whereas others exhibited significant inactivation. A similar variability in inactivation was observed in native channels from bovine chromaffin cells. In individual chromaffin cells, the amount of inactivation exhibited by N-type channels was correlated with the inactivation of P/Q-type channels, suggesting a shared mechanism. Our results with recombinant channels with known beta subunit composition indicated that inactivation could be dynamically regulated, possibly by alterations in beta subunit palmitoylation, Tunicamycin, which inhibits palmitoylation, increased steady-state inactivation of Ca2+ channels in chromaffin cells. Cerulenin, another drug that inhibits palmitoylation, also increased inactivation, Tunicamycin produced a similar effect on recombinant N-type Ca2+ channels containing beta(2a) but not beta(2b) or beta(2a) subunits mutated to be palmitoylation deficient, Our results suggest that Ca2+ channels containing beta(2a) subunits may be regulated by dynamic palmitoylation.
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