Distinct calcium channels are generated by alternative splicing and are differentially expressed in the mammalian CNS

Snutch, Terry P.; Tomlinson, W.Jeffrey; Leonard, John P.; Gilbert, Mary

doi:10.1016/0896-6273(91)90073-9

Cited by 346 publications

(215 citation statements)

References 43 publications

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“…cDNAs encoding Ca 2ϩ channel subunits ␣ 1A [rbA isoform, (19)] and ␤ 1b were cloned in pMT2XS (8), ␣ 1C [rbC-II isoform (18)] in pZem229, ␣ 2 ␦ (21) in pZEM228, and CD8 in EBPpcD. tsA-201 cells were transfected with the ␣ 1 , ␣ 2 ␦, and ␤ cDNAs in 1:1:1 molar ratios plus CD8 in either calcium phosphate or lipofectamine (Stratagene) and incubated for at least 48 h. Positively transfected cells were identified by labeling with anti-CD8 antibody tagged with fluorophore and analyzed by whole-cell patch clamp as described (14,22).…”

Section: Methodsmentioning

confidence: 99%

“…A related consensus sequence is within or adjacent to the region of the COOH terminus of inwardly rectifying K ϩ channels which is implicated in binding and regulation by G␤␥ subunits (16,17). It is also found in the intracellular loops connecting domains I and II of ␣ 1A and ␣ 1B , which are modulated by G␤␥, but not in the corresponding segment of ␣ 1C , which is not modulated by this pathway (18)(19)(20). Thus, this consensus sequence could be involved in G protein modulation of Ca 2ϩ channels.…”

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confidence: 99%

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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

Herlitze

Hockerman

Scheuer

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

193

176

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Synaptic transmission is regulated by G protein-coupled receptors whose activation releases G protein ␤␥ subunits that modulate presynaptic Ca 2؉ channels. The sequence motif QXXER has been proposed to be involved in the interaction between G protein ␤␥ subunits and target proteins including adenylyl cyclase 2. This motif is present in the intracellular loop connecting domains I and II (L I-II ) of Ca 2؉ channel ␣ 1A subunits, which are modulated by G proteins, but not in ␣ 1C subunits, which are not modulated. Peptides containing the QXXER motif from adenylate cyclase 2 or from ␣ 1A block G protein modulation but a mutant peptide containing the sequence AXXAA does not, suggesting that the QXXER-containing peptide from ␣ 1A can competitively inhibit G␤␥ modulation. Conversion of the R in the QQIER sequence of ␣ 1A to E as in ␣ 1C 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 ␣ 1C to R has opposite effects on voltage-dependent inactivation, although the changes are not as large as those for ␣ 1A . Mutation of the QQIER sequence in ␣ 1A to QQIEE enhanced G protein modulation, and mutation to QQLEE as in ␣ 1C greatly reduced G protein modulation and increased the rate of reversal of G protein effects. These results indicate that the QXXER motif in L I-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 inf luence on modulation by G␤␥. Overlap of this motif with the consensus sequence for binding of Ca 2؉ channel ␤ subunits suggests that this region of L I-II is important for three different modulatory inf luences on Ca 2؉ channel activity.Neuronal voltage-gated Ca 2ϩ channels are involved in multiple cellular functions including neurotranstransmitter release, Ca 2ϩ -mediated regulatory processes, and generation of dendritic action potentials. They consist of complexes of a poreforming ␣ 1 subunit of 190-250 kDa in association with ␣ 2 ␦ and ␤ subunits (1, 2). Electrophysiological and pharmacological studies distinguish at least six classes of Ca 2ϩ channel currents designated L-, N-, P-, Q-, R-, and T-type (2, 3). Ca 2ϩ channels containing ␣ 1C or ␣ 1D subunits are thought to be responsible for L-type currents, ␣ 1B for N-type currents, and ␣ 1A for both P-and Q-type calcium currents (2, 4). A major goal of current research is to correlate the observed differences among the properties of these channel types with the structures of their ␣ 1 subunits.P͞Q-type and N-type Ca 2ϩ channels containing ␣ 1A or ␣ 1B subunits differ from L-type Ca 2ϩ channels containing ␣ 1C or ␣ 1D subunits in voltage-dependent inactivation (5-8) and in modulation by G proteins (9). Voltage-dependent inactivation of L-type Ca 2ϩ channels containing cloned ␣ 1C is slower than inactivation of P͞Q-type Ca 2ϩ channels containing cloned ␣ 1A expressed with the same auxiliary subun...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Molecular determinants of inactivation and G protein modulation in the intracellular loop connecting domains I and II of the calcium channel α _1A subunit

Herlitze

Hockerman

Scheuer

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

193

176

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“…Recently, several laboratories have isolated cDNA clones corresponding to multiple forms of the al subunit of the voltage-sensitive calcium channel from brain [lO-121. Analysis of these brain cDNAs further revealed that the brain al subunit isoforms with sequence similarity to the skeletal muscle Ca2+ channel, which are produced by a family of related genes [13], encode the DHP-sensitive Ca" channels [14]. We and others have isolated a novel brain isoform of the DHPsensitive Ca"' channel or1 subunit cDNA (DHPR-B in [I 51; RBal in [16]) whose primary structure is significantly different from its skeletal and cardiac muscle counterparts.…”

Section: Introductionmentioning

confidence: 99%

Expression of dihydropyridine‐sensitive brain calcium channels in the rat central nervous system

et al. 1992

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WC have localized dihydropyridine (DHP)-sensitive calcium channels in rat brain by in situ hybridization and immunohistochemistry. The mRNA for the dihydropyridine-sensitive calcium channel al subunit (DHPR-B) is prominently tocalized in neuronal cells in the olfactory bulb, dentate gyrus, hippooampus, arcuate nucleus, paraventricular nucleus, vcntromcdial nucleus, cerebral cortex, superior colliculus and the cerebellar Purkinje cell layer. Strong expression of DHPR-B mRNA was also found in the pituitary and pincal glands. DHP-sensitive calcium channel 01 subunit distribution has also been examined immunohistochcmically with polyclonal antibodies raised agGnst synthetic pptides specific for the DHPR-B al subunit protein. The results from immunohistochemistry were in good aSmemcnt with those from in situ hybridization. Thus, qional distribution and localization of DHPR-B mRNA and rl subunit protein in rat brain suggest that this type of DHP-sensitive brain calcium cbanncl may play an important role in excitation-secretion coupling functions in the neuroendocrine system.

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“…To play a privileged role in activity-dependent gene expression, L-type calcium channels would be localized to these regions, to the exclusion of other calcium entry routes. ␣ 1C (Ca V 1.2), the principal subunit of a large proportion of L-type calcium channels expressed in brain, ends with the PDZ interaction sequence Val-Ser-Asn-Leu (VSNL) (Koch et al, 1990;Snutch et al, 1991). VSNL promotes ␣ 1C interactions with at least two PDZ domain proteins, channelinteracting PDZ domain protein and neuronal interleukin-16 (Kurschner et al, 1998;Kurschner and Yuzaki, 1999).…”

Section: Introductionmentioning

confidence: 99%

Interactions with PDZ Proteins Are Required for L-Type Calcium Channels to Activate cAMP Response Element-Binding Protein-Dependent Gene Expression

et al. 2003

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After brief periods of heightened stimulation, calcium entry through L-type calcium channels leads to activation of the transcription factor cAMP response element-binding protein (CREB) and CRE-dependent transcription. Many of the details surrounding the mechanism by which L-type calcium channels are privileged in signaling to CREB, to the exclusion of other calcium entry pathways, has remained unclear. We hypothesized that the PDZ interaction sequence contained within the last four amino acids of the calcium channel

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Distinct calcium channels are generated by alternative splicing and are differentially expressed in the mammalian CNS

Cited by 346 publications

References 43 publications

Molecular determinants of inactivation and G protein modulation in the intracellular loop connecting domains I and II of the calcium channel α _1A subunit

Molecular determinants of inactivation and G protein modulation in the intracellular loop connecting domains I and II of the calcium channel α _1A subunit

Expression of dihydropyridine‐sensitive brain calcium channels in the rat central nervous system

Interactions with PDZ Proteins Are Required for L-Type Calcium Channels to Activate cAMP Response Element-Binding Protein-Dependent Gene Expression

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Distinct calcium channels are generated by alternative splicing and are differentially expressed in the mammalian CNS

Cited by 346 publications

References 43 publications

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

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

Expression of dihydropyridine‐sensitive brain calcium channels in the rat central nervous system

Interactions with PDZ Proteins Are Required for L-Type Calcium Channels to Activate cAMP Response Element-Binding Protein-Dependent Gene Expression

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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

Molecular determinants of inactivation and G protein modulation in the intracellular loop connecting domains I and II of the calcium channel α _1A subunit