A Single Gβ Subunit Locus Controls Cross-talk between Protein Kinase C and G Protein Regulation of N-type Calcium Channels

The modulation of N-type calcium channels is a key factor in the control of neurotransmitter release. Whereas N-type channels are inhibited by Gβγ subunits in a G protein β-isoform-dependent manner, channel activity is typically stimulated by activation of protein kinase C (PKC). In addition, there is cross-talk among these pathways, such that PKC-dependent phosphorylation of the Gβγ target site on the N-type channel antagonizes subsequent G protein inhibition, albeit only for Gβ1-mediated responses. The molecular mechanisms that control this G protein β subunit subtype-specific regulation have not been described. Here, we show that G protein inhibition of N-type calcium channels is critically dependent on two separate but adjacent ∼20-amino acid regions of the Gβ subunit, plus a highly conserved Asn-Tyr-Val motif. These regions are distinct from those implicated previously in Gβγ signaling to other effectors such as G protein-coupled inward rectifier potassium channels, phospholipase β2, and adenylyl cyclase, thus raising the possibility that the specificity for G protein signaling to calcium channels might rely on unique G protein structural determinants. In addition, we identify a highly specific locus on the Gβ1 subunit that serves as a molecular detector of PKC-dependent phosphorylation of the G protein target site on the N-type channel α1 subunit, thus providing for a molecular basis for G protein-PKC cross-talk. Overall, our results significantly advance our understanding of the molecular details underlying the integration of G protein and PKC signaling pathways at the level of the N-type calcium channel α1 subunit. The modulation of N-type calcium channels is a key factor in the control of neurotransmitter release. Whereas N-type channels are inhibited by Gβγ subunits in a G protein β-isoform-dependent manner, channel activity is typically stimulated by activation of protein kinase C (PKC). In addition, there is cross-talk among these pathways, such that PKC-dependent phosphorylation of the Gβγ target site on the N-type channel antagonizes subsequent G protein inhibition, albeit only for Gβ1-mediated responses. The molecular mechanisms that control this G protein β subunit subtype-specific regulation have not been described. Here, we show that G protein inhibition of N-type calcium channels is critically dependent on two separate but adjacent ∼20-amino acid regions of the Gβ subunit, plus a highly conserved Asn-Tyr-Val motif. These regions are distinct from those implicated previously in Gβγ signaling to other effectors such as G protein-coupled inward rectifier potassium channels, phospholipase β2, and adenylyl cyclase, thus raising the possibility that the specificity for G protein signaling to calcium channels might rely on unique G protein structural determinants. In addition, we identify a highly specific locus on the Gβ1 subunit that serves as a molecular detector of PKC-dependent phosphorylation of the G protein target site on the N-type channel α1 subunit, thus providing for a molecular basis for G protein-PKC cross-talk. Overall, our results significantly advance our understanding of the molecular details underlying the integration of G protein and PKC signaling pathways at the level of the N-type calcium channel α1 subunit. The modulation of calcium channels at presynaptic nerve terminals is a key factor in regulating synaptic efficacy (1Wheeler G.B. Randall A. Tsien R.W. Science. 1994; 264: 107-111Crossref PubMed Scopus (828) Google Scholar, 2Dunlap K. Luebke J.I. Turnerm T.J. Trends Neurosci. 1995; 18: 89-98Abstract Full Text PDF PubMed Scopus (865) Google Scholar). It is now well established that the activation of G protein-coupled receptors inhibits presynaptic calcium channel activity and thus neurotransmitter release (3Zamponi G.W. Cell Biochem. Biophys. 2001; 34: 79-94Crossref PubMed Scopus (41) Google Scholar). G protein inhibition of both N-type and P/Q-type calcium channels appears to be exclusively mediated by the G protein βγ subunit (4Ikeda S.R. Nature. 1996; 380: 255-258Crossref PubMed Scopus (705) Google Scholar, 5Herlitze S. Garcia D.E. Mackie K. Hille B. Scheuer T. Catterall W.A. Nature. 1996; 280: 258-262Crossref Scopus (693) Google Scholar), with the Gβ subunit being the main determinant of calcium channel inhibition. Putative G protein βγ subunit interaction sites have been identified within the intracellular loop linking domains I and II of the calcium channel α1 subunit (6DeWaard M. Liu H. Walker D. Scott V.E. Gurnett C.A. Campbell K.P. Nature. 1997; 385: 446-450Crossref PubMed Scopus (368) Google Scholar, 7Zamponi G.W. Bourinet E. Nelson D. Nargeot J. Snutch T.P. Nature. 1997; 385: 242-246Crossref Scopus (402) Google Scholar, 8Page K.M. Stephens G.J. Berrow N.S. Dolphin A.C. J. Neurosci. 1997; 17: 1330-1338Crossref PubMed Google Scholar), as well as in the C-terminal region (9Qin N. Platano D. Olcese R. Stefani E. Birnbaumer L. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 8866-8871Crossref PubMed Scopus (206) Google Scholar). To date, five different types of G protein β subunits have been identified and shown to mediate varying effects on native and transiently expressed N-type calcium channels (10Garcia D.E. Li B. Garcia-Ferreiro R.E. Hernandez-Ochoa E.O. Yan K. Gautam N. Catterall W.A. Mackie K. Hille B. J. Neurosci. 1998; 18: 9163-9170Crossref PubMed Google Scholar, 11Ruiz-Velasco V. Ikeda S.R. J. Neurosci. 2000; 20: 2183-2191Crossref PubMed Google Scholar). Moreover, N-type and P/Q-type calcium channels appear to be differentially modulated by different types of G protein β subunits (12Arnot M.I. Stotz S.C. Jarvis S.E. Zamponi G.W. J. Physiol. 2000; 527: 203-212Crossref PubMed Scopus (57) Google Scholar), thus providing for a mechanism by which different G protein-coupled receptors may selectively regulate individual presynaptic calcium channel subtypes. In contrast, activation of protein kinase C (PKC) 1The abbreviations used are: PKC, protein kinase C; GIRK, G protein-coupled inward rectifier potassium; EGFP, enhanced green fluorescent protein; PP, prepulse; PMA, phorbol 12-myristate 13-acetate; ANOVA, analysis of variance.1The abbreviations used are: PKC, protein kinase C; GIRK, G protein-coupled inward rectifier potassium; EGFP, enhanced green fluorescent protein; PP, prepulse; PMA, phorbol 12-myristate 13-acetate; ANOVA, analysis of variance. results in an up-regulation of N-type channel activity (13Stea A. Soong T.W. Snutch T.P. Neuron. 1995; 15: 929-940Abstract Full Text PDF PubMed Scopus (194) Google Scholar, 14Barrett C.F. Rittenhouse A.R. J. Gen. Physiol. 2000; 115: 277-286Crossref PubMed Scopus (60) Google Scholar). There is a complex interplay between PKC and G protein pathways such that activation of PKC antagonizes subsequent receptor-mediated G protein inhibition of presynaptic calcium channels (15Swartz K.J. Neuron. 1993; 11: 305-320Abstract Full Text PDF PubMed Scopus (186) Google Scholar, 16Swartz K.J. Merrit A. Bean B.P. Lovinger D.M. Nature. 1993; 361: 165-168Crossref PubMed Scopus (177) Google Scholar). This effect is mediated via PKC-dependent phosphorylation of a single threonine residue located in the G protein interaction site within the domain I-II linker region of the N-type calcium channel α1 subunit (17Hamid J. Nelson D. Spaetgens R. Dubel S.J. Snutch T.P. Zamponi G.W. J. Biol. Chem. 1999; 278: 6195-6202Abstract Full Text Full Text PDF Scopus (111) Google Scholar), thus allowing the channel protein to integrate multiple modulatory inputs. Interestingly, this cross-talk between G protein and PKC pathways appears to be a selective feature of the G protein β1 subunit, thus allowing PKC to selectively antagonize G protein inhibition mediated by a subset of (i.e. predominantly Gβ1-coupled) receptors (18Cooper C.B. Arnot M.I. Feng Z.P. Jarvis S.E. Hamid J. Zamponi G.W. J. Biol. Chem. 2000; 275: 40777-40781Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). However, although calcium channel structural determinants of G protein regulation and PKC cross-talk have received considerable attention (3Zamponi G.W. Cell Biochem. Biophys. 2001; 34: 79-94Crossref PubMed Scopus (41) Google Scholar), there is relatively scant information that concerns the G protein structural determinants that underlie N-type channel regulation and PKC-G protein cross-talk. Alanine mutagenesis of Gβ to with Gβ to a of calcium channels, adenylyl cyclase, channels, and phospholipase H. E. R. R. Science. 1998; 280: PubMed Scopus Google Scholar, J. J. Gen. Physiol. PubMed Scopus Google Scholar). This that there may be in the G protein β subunit structural determinants that control the both within the G protein complex and with signaling H. E. R. R. Science. 1998; 280: PubMed Scopus Google identified acid and on the Gβ1 subunit to the of Gβ1 to N-type calcium In addition, mutagenesis of two and in an to regulate N-type However, these are conserved types of G protein β subunit which that for the effects of different types of Gβ subunits on calcium channel Gβ structural determinants control G protein modulation of N-type Here, we and G protein β subunits to identify G protein structural determinants that control on N-type identify a of acid in the Gβ1 subunit that is for N-type channel In addition, we cross-talk to a single locus on the Gβ1 subunit, thus a molecular that the G to a N-type calcium In this our a in our understanding of the complex interplay between G protein and PKC regulation of presynaptic calcium channel Gβ1 and and Gβ1 and subunits by previously (12Arnot M.I. Stotz S.C. Jarvis S.E. Zamponi G.W. J. Physiol. 2000; 527: 203-212Crossref PubMed Scopus (57) Google Scholar, Z.P. Arnot M.I. Zamponi G.W. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). calcium channel subunits by Snutch of and the N-type channel previously (17Hamid J. Nelson D. Spaetgens R. Dubel S.J. Snutch T.P. Zamponi G.W. J. Biol. Chem. 1999; 278: 6195-6202Abstract Full Text Full Text PDF Scopus (111) Google Scholar). in two an of and sites both Gβ1 and at the mutagenesis In the region with the and sites and and the of and sites in the this the of different regions (i.e. and to Gβ1 between Gβ1 and and of the via that and in Gβ1 to and in of via Gβ subunits and the of as and the of the these used to and of the the as a in the the two to at those The two in and to of with only the and in the used for and in the of the by to that the in Gβ1 and in both Gβ1 and the as The of the and the of mutagenesis via Gβ C-terminal G protein β subunits from the previously sites and in the and (12Arnot M.I. Stotz S.C. Jarvis S.E. Zamponi G.W. J. Physiol. 2000; 527: 203-212Crossref PubMed Scopus (57) Google and the within the with both and and of and with calcium as by previously in Z.P. Arnot M.I. Zamponi G.W. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). In calcium channels, calcium channel α1 subunits with and an in the G plus of Gβ channels, and subunits used of calcium channel To from the are in a these such that appear and to a of with an to a with a and of The by The at and the of the the by from to a of G protein inhibition by of a for only with used for The of of G protein inhibition as the of and the and the of a G protein β subunit to N-type The the and in activation of protein kinase in at a and the at a of via a and an of potassium and with The and with these the for potassium is channel activity by the at by an of a from to inward used for and by a to the inward from to In this there between and not and the are in as of we the activity in the of Gβ of the and in analysis in via as via with a for on the at the and with the N-type calcium channel and and G protein β of in a and with an an The stimulated with an for and that with Z.P. Arnot M.I. Zamponi G.W. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). of N-type by Gβ1 have shown previously that N-type calcium channels are inhibited by Gβ1 subunits have effect on activity M.I. Stotz S.C. Jarvis S.E. Zamponi G.W. J. Physiol. 2000; 527: 203-212Crossref PubMed Scopus (57) Google To key G protein β subunit structural determinants that control calcium channel inhibition, the effects used as the basis for a the Gβ1 and subunits regions that in for The with N-type calcium channels, the subunit, and an and G protein inhibition by of as and shown in Gβ1 a inhibition as by a in the of the the of Gβ1 with in the of Gβ1 to N-type channels, the that Gβ1 and only and in these two In contrast, as in of with in with other the of to that in the of that with not significantly from G are To the possibility that the of modulation might be to the of to of the Gβ subunit we of the and key G and via shown in the of the and G protein subunits in the that are expressed and in Moreover, the that of the Gβ that the effects are not to an of to Gβγ In addition, we have shown previously via and that of G protein results in of Gβ in to a of G protein N-type calcium channels Z.P. Arnot M.I. Zamponi G.W. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). these that the to G protein inhibition with not to a of Overall, our with the of that although the and C-terminal regions of Gβ are not determinants of G protein inhibition of N-type channels, regions between and are for G protein inhibition. To the G protein β subunit structural determinants of N-type channel we with in regions and shown in Gβ1 with in the of G protein inhibition. of within these two regions that of regions and not the of Gβ1 to N-type channel the the a enhanced to N-type channel In contrast, of of an and is highly conserved in G protein β subunits with the of with (i.e. the of Gβ1 to N-type calcium analysis for is shown in shown in and of and the of Gβ1 to N-type calcium channels, of Gβ1 there appear to be at separate regions that are for the effect of Gβ1 and on N-type calcium channel It is that these effects have from a of Gβ1 subunit of the of Gβ1 activity for a of the that (i.e. and To that the effects of the specific by we to a of in which regions in with Gβ1 and However, the not in G protein inhibition This that of may of the identified which be to an we two in which and of Gβ1 with These are located within the and on the on the Gβ1 of with in a of the of and of to in an of to These that single acid in at two of the identified regions are to the of Gβ1 to N-type calcium channels, with the that the of the to regulate channel activity not from structural analysis of in the G protein β1 subunit. from the N-type calcium and G protein β subunit and The as in the to that the of the in the shown the of of the N-type calcium channels with the in The to The the level of modulation with the G protein subunits are and as in the to and of the the of the of with calcium channels in the of Gβ1 the that the of with acid antagonizes Gβ1 but effect on modulation by the of the regions of Gβ1 The shown as are unique to effect of mutagenesis of unique Gβ1 in PKC-G protein cross-talk. that the effect of the on G protein inhibition is mutagenesis of and of G protein-PKC cross-talk the subunit of and of the are the and the between the of inhibition with the and N-type effect of protein kinase C activation on the of the of and In the of to and of that significantly the effect of but not that of the Gβ1 The are the and the the at the level To the of those Gβ that to regulate N-type channel we a of with and subunits in with Gβ and the via a the of we on the key and that the regions in N-type channel and the shown in of in the of Gβ subunits in with in T. L. H. D.E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of Gβ1 subunits in a in by and in with a T. L. H. D.E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), subunits channels, thus that subunits are expressed in our single of the and Gβ subunits mediated a in activity to a level with that with we that the of effects of these on N-type channel activity not from protein protein G PKC have shown previously that PKC-dependent phosphorylation of in the calcium channel I-II linker selectively antagonizes the Gβ1-mediated inhibition of N-type channel activity (18Cooper C.B. Arnot M.I. Feng Z.P. Jarvis S.E. Hamid J. Zamponi G.W. J. Biol. Chem. 2000; 275: 40777-40781Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). that of this effect be by with acid (17Hamid J. Nelson D. Spaetgens R. Dubel S.J. Snutch T.P. Zamponi G.W. J. Biol. Chem. 1999; 278: 6195-6202Abstract Full Text Full Text PDF Scopus (111) Google Scholar, C.B. Arnot M.I. Feng Z.P. Jarvis S.E. Hamid J. Zamponi G.W. J. Biol. Chem. 2000; 275: 40777-40781Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar), thus the for activation of PKC and the for specificity of PKC a the of Gβ1 to Gβ1 with to N-type channel regulation we the PKC cross-talk be with this the the of Gβ1 to N-type channel the to the of the thus that a key Gβ1 structural determinant is located in the the PKC cross-talk is only with we the acid for unique to this subunit shown in of with acid effect on cross-talk. In contrast, of and with in the effects of the I-II linker that both of these the of a within the I-II linker G domain G.W. Bourinet E. Nelson D. Nargeot J. Snutch T.P. Nature. 1997; 385: 242-246Crossref Scopus (402) Google Scholar). be to cross-talk other G protein subunits by in To this we mutagenesis in the subunit N-type channels but is not by (18Cooper C.B. Arnot M.I. Feng Z.P. Jarvis S.E. Hamid J. Zamponi G.W. J. Biol. Chem. 2000; 275: 40777-40781Abstract Full Text Full Text PDF PubMed Scopus (51) Google and the of the to and N-type with our the subunit inhibited the channel significantly the channel To that the not an of the calcium channel we the shown in and activation of PKC via of the phorbol the of of and in activation of PKC not the of with the In contrast, mutagenesis of and to Gβ1 (i.e. the cross-talk such that the of significantly the of these that the Gβ1 subunit a locus of two that this subunit to the of a as a on the N-type calcium channel α1 subunit. with the key Gβ subunit regions that are for N-type calcium channel that on mutagenesis of Gβ subunit to be in subunit (i.e. H. E. R. R. Science. 1998; 280: PubMed Scopus Google and J. J. Gen. Physiol. PubMed Scopus Google Scholar), we a that on the of Gβ1 and to N-type calcium show that mutagenesis of and a that is highly conserved in Gβ subunits other G protein regulation of the N-type This region is located of the interaction domain D.E. E. S.R. 1995; Full Text PDF PubMed Scopus Google and J. A. Nature. 1996; PubMed Scopus Google and and not been previously identified as an domain on the Gβ1 subunit. G protein inhibition of Gβ1 and the G protein β subunit structural determinants that control signaling to N-type calcium channels appear to be different from those implicated in to other such as adenylyl cyclase, channels, phospholipase (i.e. and and H. E. R. R. Science. 1998; 280: PubMed Scopus Google Scholar, T. L. H. D.E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, K. Gautam N. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, K. Gautam N. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, Li J. A. J. J. H. R. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google Scholar, K. Li S. T. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, E. Li J. S. R. Science. 1999; PubMed Scopus Google Scholar, H. S. T. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, T. V. H. D.E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). However, in of specific of the of our on effectors other channels, is to the regions identified in our are exclusively in signaling to N-type regions and and acid are in Gβ1 and and not for the effects conserved and which implicated previously as being for N-type channel H. E. R. R. Science. 1998; 280: PubMed Scopus Google Scholar). of the of the in regions and a in which of the appear to be in a at the protein to that the interaction domain these and to be for G protein inhibition. The of with to be in with is with a of other Gβγ effectors that with the interaction region of the G protein complex H. E. R. R. Science. 1998; 280: PubMed Scopus Google Scholar). It is to that our not with that mutagenesis of conserved within the region Gβ1 inhibition of N-type calcium channels H. E. R. R. Science. 1998; 280: PubMed Scopus Google Scholar, T. V. H. D.E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), our to the molecular basis of the between Gβ1 and regulation of N-type channels of that to N-type channels inhibition. The that our of not to mediate G protein inhibition of the channel is with the of structural determinants. of of Gβ1 with in a of the of N-type channels inhibition. This of a residue in which to been to N-type channel inhibition H. E. R. R. Science. 1998; 280: PubMed Scopus Google Scholar), in with This region to the been to G protein inhibition T. V. H. D.E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). that the mediated G protein inhibition appears at with this is that the effects of the are by the effect of mutagenesis of individual be to the of and in calcium channel inhibition. our that a of residue and in regions and of Gβ1 is for N-type channel inhibition, with and being of of G protein-PKC N-type calcium channel at separate sites for two of these sites are by ∼20-amino acid within the domain I-II linker (6DeWaard M. Liu H. Walker D. Scott V.E. Gurnett C.A. Campbell K.P. Nature. 1997; 385: 446-450Crossref PubMed Scopus (368) Google Scholar, 7Zamponi G.W. Bourinet E. Nelson D. Nargeot J. Snutch T.P. Nature. 1997; 385: 242-246Crossref Scopus (402) Google plus an site in the C-terminal region (9Qin N. Platano D. Olcese R. Stefani E. Birnbaumer L. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 8866-8871Crossref PubMed Scopus (206) Google Scholar). The that multiple regions within the Gβγ subunit to be for G protein inhibition is with the of multiple G protein sites on the N-type channel α1 subunit. The of the two I-II linker Gβγ regions the PKC phosphorylation site by residue G.W. Bourinet E. Nelson D. Nargeot J. Snutch T.P. Nature. 1997; 385: 242-246Crossref Scopus (402) Google Scholar, J. Nelson D. Spaetgens R. Dubel S.J. Snutch T.P. Zamponi G.W. J. Biol. Chem. 1999; 278: 6195-6202Abstract Full Text Full Text PDF Scopus (111) Google Scholar). In phosphorylation of this site Gβγ to this region G.W. Bourinet E. Nelson D. Nargeot J. Snutch T.P. Nature. 1997; 385: 242-246Crossref Scopus (402) Google Scholar), and of with acid of phosphorylation (17Hamid J. Nelson D. Spaetgens R. Dubel S.J. Snutch T.P. Zamponi G.W. J. Biol. Chem. 1999; 278: 6195-6202Abstract Full Text Full Text PDF Scopus (111) Google Scholar, C.B. Arnot M.I. Feng Z.P. Jarvis S.E. Hamid J. Zamponi G.W. J. Biol. Chem. 2000; 275: 40777-40781Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). the a of G protein β subunit determinants that to the cross-talk to to activation of PKC via that the of the Gβ1 subunit and for the of this acid residue the phosphorylation of the native threonine The of this on the Gβ1 subunit is this region is not typically with to of the Gβγ effectors the of these two in G protein-PKC cross-talk appears to be highly of these the subunit that is of phosphorylation of (18Cooper C.B. Arnot M.I. Feng Z.P. Jarvis S.E. Hamid J. Zamponi G.W. J. Biol. Chem. 2000; 275: 40777-40781Abstract Full Text Full Text PDF PubMed Scopus (51) Google the cross-talk at this only the mechanism by which Gβ and to the N-type channel I-II linker the have shown previously that of Gβγ to this region results in a of G protein inhibition G.W. Bourinet E. Nelson D. Nargeot J. Snutch T.P. Nature. 1997; 385: 242-246Crossref Scopus (402) Google Scholar). there is a interaction between Gβ subunit and the phosphorylation only to Gβγ G protein inhibition is but not activation of PKC (17Hamid J. Nelson D. Spaetgens R. Dubel S.J. Snutch T.P. Zamponi G.W. J. Biol. Chem. 1999; 278: 6195-6202Abstract Full Text Full Text PDF Scopus (111) Google Scholar, C.B. Arnot M.I. Feng Z.P. Jarvis S.E. Hamid J. Zamponi G.W. J. Biol. Chem. 2000; 275: 40777-40781Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). the other the with the with the of in that this region of Gβ is not a determinant of G protein on N-type between and the acid of among Gβ subunits is highly conserved This the possibility that this region with the N-type channel I-II linker but that phosphorylation of might via an interaction with Gβ1 and thus for the G protein inhibition activation of mutagenesis of be to this that a site and with the calcium channel I-II linker region this the as to which region of the N-type channel with the in (i.e. and the N-type channel two domains for a region in the C-terminal (9Qin N. Platano D. Olcese R. Stefani E. Birnbaumer L. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 8866-8871Crossref PubMed Scopus (206) Google and a I-II linker site of (6DeWaard M. Liu H. Walker D. Scott V.E. Gurnett C.A. Campbell K.P. Nature. 1997; 385: 446-450Crossref PubMed Scopus (368) Google Scholar, 7Zamponi G.W. Bourinet E. Nelson D. Nargeot J. Snutch T.P. Nature. 1997; 385: 242-246Crossref Scopus (402) Google Scholar). of the Gβγ to this region G protein inhibition G.W. Bourinet E. Nelson D. Nargeot J. Snutch T.P. Nature. 1997; 385: 242-246Crossref Scopus (402) Google Scholar), of the C-terminal site only a effect (17Hamid J. Nelson D. Spaetgens R. Dubel S.J. Snutch T.P. Zamponi G.W. J. Biol. Chem. 1999; 278: 6195-6202Abstract Full Text Full Text PDF Scopus (111) Google Scholar). that of these Gβ1 subunit domains with G protein we thus the I-II linker site the C as a a in which Gβγ is in of two distinct sites on the Gβ protein with two separate regions within the calcium channel I-II In this the interaction between the I-II linker residue and on the Gβ1 subunit the thus the of G protein inhibition of the The C of the N-type channel might G protein by with previously identified in the interaction our a in our understanding of the molecular basis underlying cross-talk between G protein and PKC regulation of N-type calcium The of a specific site on the Gβ subunit that serves as a molecular detector of PKC-dependent phosphorylation of the N-type calcium channel a unique of multiple signaling pathways at the level of a This may for regulation of N-type calcium channel activity synaptic Snutch for providing calcium channel and for providing Scott Jarvis for with

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