NDLI: Molecular determinants of inactivation and G protein modulation in the intracellular loop connecting domains I and II of the calcium channel α1A subunit

Content Provider	PubMed Central
Author	Herlitze, Stefan Hockerman, Gregory h. Scheuer, Todd Catterall, William a.
Copyright Year	1997
Abstract	Synaptic transmission is regulated by G protein-coupled receptors whose activation releases G protein βγ subunits that modulate presynaptic Ca2+ channels. The sequence motif QXXER has been proposed to be involved in the interaction between G protein βγ subunits and target proteins including adenylyl cyclase 2. This motif is present in the intracellular loop connecting domains I and II (LI-II) of Ca2+ channel α1A subunits, which are modulated by G proteins, but not in α1C subunits, which are not modulated. Peptides containing the QXXER motif from adenylate cyclase 2 or from α1A block G protein modulation but a mutant peptide containing the sequence AXXAA does not, suggesting that the QXXER-containing peptide from α1A can competitively inhibit Gβγ modulation. Conversion of the R in the QQIER sequence of α1A to E as in α1C slows channel inactivation and shifts the voltage dependence of steady-state inactivation to more positive membrane potentials. Conversion of the final E in the QQLEE sequence of α1C to R has opposite effects on voltage-dependent inactivation, although the changes are not as large as those for α1A. Mutation of the QQIER sequence in α1A to QQIEE enhanced G protein modulation, and mutation to QQLEE as in α1C greatly reduced G protein modulation and increased the rate of reversal of G protein effects. These results indicate that the QXXER motif in LI-II is an important determinant of both voltage-dependent inactivation and G protein modulation, and that the amino acid in the third position of this motif has an unexpectedly large influence on modulation by Gβγ. Overlap of this motif with the consensus sequence for binding of Ca2+ channel β subunits suggests that this region of LI-II is important for three different modulatory influences on Ca2+ channel activity.
Starting Page	1512
File Format	PDF
ISSN	10916490
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	4
Volume Number	94
Language	English
Publisher	The National Academy of Sciences of the USA
Publisher Date	1997-02-18
Access Restriction	Open
Rights Holder	The National Academy of Sciences of the USA
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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Molecular determinants of inactivation and G protein modulation in the intracellular loop connecting domains I and II of the calcium channel $α_{1A} subunit$

Scanning mutagenesis of the I-II loop of the Cav2.2 calcium channel identifies residues Arginine 376 and Valine 416 as molecular determinants of voltage dependent G protein inhibition

Scanning mutagenesis of the I-II loop of the Cav2.2 calcium channel identifies residues Arginine 376 and Valine 416 as molecular determinants of voltage dependent G protein inhibition

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Molecular determinants of inactivation and G protein modulation in the intracellular loop connecting domains I and II of the calcium channel $α_{1A} subunit$

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