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The HOOK-domain between the SH3 and the GK domains of Ca-v beta subunits contains key determinants controlling calcium channel inactivation

Richards, MW; Leroy, J; Pratt, WS; Dolphin, AC; (2007) The HOOK-domain between the SH3 and the GK domains of Ca-v beta subunits contains key determinants controlling calcium channel inactivation. CHANNELS , 1 (2) 92 - 101.

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Abstract

Ca-v beta subunits of voltage-gated calcium channels contain two conserved domains, a src-homology-3 (SH3)-domain and a guanylate kinase-like (GK)-domain. The SH3-domain is split, with its final (fifth) beta-strand separated from the rest of the domain by an intervening sequence termed the HOOK-domain, whose sequence varies between Ca-v beta subunits. Here we have been guided by the recent structural studies of Ca-v beta subunits in the design of specific truncated constructs, with the goal of investigating the role of the HOOK-domain of Ca-v beta subunits in the modulation of inactivation of N-type calcium channels. We have coexpressed the beta subunit constructs with Ca(v)2.2 and alpha(2)delta-2, using the N-terminally palmitoylated beta(2a) subunit, because it supports very little voltage-dependent inactivation, and made comparisons with beta(1b) domains. Deletion of the variable region of the beta(2a) HOOK-domain resulted in currents with a rapidly inactivating component, and additional mutation of the beta(2a) palmitoylation motif further enhanced inactivation. The isolated GK-domain of beta(2a) alone enhanced current amplitude, but the currents were rapidly and completely inactivating. When the beta(2a)-GK-domain construct was extended proximally, by including the HOOK-domain and the e-strand of the SH3-domain, inactivation was about four-fold slower than in the absence of the HOOK domain. When the SH3-domain of beta(2a) truncated prior to the HOOK-domain was coexpressed with the (HOOK+epsilon SH3+GK)-domain of beta(2a), all the properties of beta(2a) were restored, in terms of loss of inactivation. Furthermore, removal of the HOOK sequence from the (HOOK+epsilon SH3+GK)-beta(2a) construct increased inactivation. Together, these results provide evidence that the HOOK domain is an important determinant of inactivation.

Type: Article
Title: The HOOK-domain between the SH3 and the GK domains of Ca-v beta subunits contains key determinants controlling calcium channel inactivation
Keywords: calcium channel, beta subunit, electrophysiology, I-II-LINKER, ALPHA(1A) SUBUNIT, MODULATION, IDENTIFICATION, PALMITOYLATION, TRYPTOPHAN, TERMINUS, COMPLEX, BINDING, REGION
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: http://discovery.ucl.ac.uk/id/eprint/175709
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