Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 98, Issue 8, Pages 4705-4709Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.051629098
Keywords
neuromodulation; G protein; voltage sensor; facilitation
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Funding
- PHS HHS [N522625] Funding Source: Medline
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N-type Ca2+ channels can be inhibited by neurotransmitter-induced release of G protein beta gamma subunits. Two isoforms of Ca(v)2.2 alpha (1) subunits of N-type calcium channels from rat brain (Ca(v)2.2a and Ca(v)2.2b; initially termed rbB-I and rbB-II) have different functional properties. Unmodulated Ca(v)2.2b channels are in an easily activated willing (W) state with fast activation kinetics and no prepulse facilitation. Activating C proteins shifts Ca(v)2.2b channels to a difficult to activate reluctant (R) state with slow activation kinetics; they can be returned to the W state by strong depolarization resulting in prepulse facilitation. This contrasts with Ca(v)2.2a channels, which are tonically in the R state and exhibit strong prepulse facilitation. Activating or inhibiting G proteins has no effect. Thus, the R state of Ca(v)2.2a and its reversal by prepulse facilitation are intrinsic to the channel and independent of C protein modulation. Mutating G177 in segment IS3 of Ca(v)2.2b to E as in Ca(v)2.2a converts Ca(v)2.2b tonically to the R state, insensitive to further G protein modulation. The converse substitution in Ca(v)2.2a, E177G, converts it to the W state and restores G protein modulation. We propose that negatively charged E177 in IS3 interacts with a positive charge in the IS4 voltage sensor when the channel is closed and produces the R state of Cav2.2a by a voltage sensor-trapping mechanism. C protein beta gamma subunits may produce reluctant channels by a similar molecular mechanism.
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