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Scanning Mutagenesis Reveals a Role for Serine 189 of the Heterotrimeric G-Protein Beta 1 Subunit in the Inhibition of N-Type Calcium Channels

Department of Physiology and Biophysics, Faculty of Medicine, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada

Submitted 1 March 2006; accepted in final form 3 April 2006

Direct interactions between the presynaptic N-type calcium channel and the subunit of the heterotrimeric G-protein complex cause voltage-dependent inhibition of N-type channel activity, crucially influencing neurotransmitter release and contributing to analgesia caused by opioid drugs. Previous work using chimeras of the G-protein subtypes G₁ and G₅ identified two 20–amino acid stretches of structurally contiguous residues on the G₁ subunit as critical for inhibition of the N-type channel. To identify key modulation determinants within these two structural regions, we performed scanning mutagenesis in which individual residues of the G₁ subunit were replaced by corresponding G₅ residues. Our results show that G₁ residue Ser¹⁸⁹ is critical for N-type calcium channel modulation, whereas none of the other G₁ mutations caused statistically significant effects on the ability of G₁ to inhibit N-type channels. Structural modeling shows residue 189 is surface exposed, consistent with the idea that it may form a direct contact with the N-type calcium channel ₁ subunit during binding interactions.

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