Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Alternative splicing of a beta4 subunit proline-rich motif regulates voltage-dependent gating and toxin block of Cav2.1 Ca2+ channels.
Helton TD
,
Kojetin DJ
,
Cavanagh J
,
Horne WA
.
???displayArticle.abstract???
Ca2+ channel beta subunits modify alpha1 subunit gating properties through direct interactions with intracellular linker domains. In a previous report (Helton and Horne, 2002), we showed that alternative splicing of the beta4 subunit had alpha1 subunit subtype-specific effects on Ca2+ channel activation and fast inactivation. We extend these findings in the present report to include effects on slow inactivation and block by the peptide toxin omega-conotoxin (CTx)-MVIIC. N-terminal deletion and site-directed mutagenesis experiments revealed that the effects of alternative splicing on toxin block and all aspects of gating could be attributed to a proline-rich motif found within N-terminal beta4b amino acids 10-20. Interestingly, this motif is conserved within the third postsynaptic density-95 (PSD-95)/Discs large/zona occludens-1 domain of the distantly related membrane-associated guanylate kinase homolog, PSD-95. Sequence identity of approximately 30% made possible the building of beta4a and beta4b three-dimensional structural models using PSD-95 as the target sequence. The models (1) reveal that alternative splicing of the beta4 N terminus results in dramatic differences in surface charge distribution and (2) localize the proline-rich motif of beta4b to an extended arm structure that flanks what would be the equivalent of a highly modified PSD-95 carboxylate binding loop. Northern blot analysis revealed a markedly different pattern of distribution for beta4a versus beta4b in the human CNS. Whereas beta4a is distributed throughout evolutionarily older regions of the CNS, beta4b is concentrated heavily in the forebrain. These results raise interesting questions about the functional role that alternative splicing of the beta4 subunit has played in the evolution of complex neural networks.
Abbott,
Synaptic depression and cortical gain control.
1997, Pubmed
Abbott,
Synaptic depression and cortical gain control.
1997,
Pubmed
Altschul,
Basic local alignment search tool.
1990,
Pubmed
Berjukow,
Amino acids in segment IVS6 and beta-subunit interaction support distinct conformational changes during Ca(v)2.1 inactivation.
2001,
Pubmed
,
Xenbase
Berrou,
Molecular determinants of inactivation within the I-II linker of alpha1E (CaV2.3) calcium channels.
2001,
Pubmed
,
Xenbase
Bezanilla,
The voltage sensor in voltage-dependent ion channels.
2000,
Pubmed
Bezprozvanny,
PDZ domains: More than just a glue.
2001,
Pubmed
Bezprozvanny,
Molecular determinants of the functional interaction between syntaxin and N-type Ca2+ channel gating.
2000,
Pubmed
,
Xenbase
Catterall,
Structure and regulation of voltage-gated Ca2+ channels.
2000,
Pubmed
Cha,
Atomic scale movement of the voltage-sensing region in a potassium channel measured via spectroscopy.
1999,
Pubmed
Colovos,
Verification of protein structures: patterns of nonbonded atomic interactions.
1993,
Pubmed
Cuppen,
PDZ motifs in PTP-BL and RIL bind to internal protein segments in the LIM domain protein RIL.
1998,
Pubmed
Degtiar,
Syntaxin modulation of slow inactivation of N-type calcium channels.
2000,
Pubmed
,
Xenbase
Dimitratos,
Signaling pathways are focused at specialized regions of the plasma membrane by scaffolding proteins of the MAGUK family.
1999,
Pubmed
Doyle,
Crystal structures of a complexed and peptide-free membrane protein-binding domain: molecular basis of peptide recognition by PDZ.
1996,
Pubmed
Doyle,
The structure of the potassium channel: molecular basis of K+ conduction and selectivity.
1998,
Pubmed
Ellinor,
Structural determinants of the blockade of N-type calcium channels by a peptide neurotoxin.
1994,
Pubmed
,
Xenbase
Forsythe,
Inactivation of presynaptic calcium current contributes to synaptic depression at a fast central synapse.
1998,
Pubmed
Fortune,
Short-term synaptic plasticity as a temporal filter.
2001,
Pubmed
Glauner,
Spectroscopic mapping of voltage sensor movement in the Shaker potassium channel.
1999,
Pubmed
,
Xenbase
Hanlon,
Modelling of a voltage-dependent Ca2+ channel beta subunit as a basis for understanding its functional properties.
1999,
Pubmed
Hans,
Structural elements in domain IV that influence biophysical and pharmacological properties of human alpha1A-containing high-voltage-activated calcium channels.
1999,
Pubmed
Harris,
Mechanism and role of PDZ domains in signaling complex assembly.
2001,
Pubmed
Helton,
Alternative splicing of the beta 4 subunit has alpha1 subunit subtype-specific effects on Ca2+ channel gating.
2002,
Pubmed
,
Xenbase
Horn,
A new twist in the saga of charge movement in voltage-dependent ion channels.
2000,
Pubmed
Horne,
Molecular diversity of Ca2+ channel alpha 1 subunits from the marine ray Discopyge ommata.
1993,
Pubmed
Hu,
beta 1-adrenergic receptor association with PSD-95. Inhibition of receptor internalization and facilitation of beta 1-adrenergic receptor interaction with N-methyl-D-aspartate receptors.
2000,
Pubmed
Irie,
Binding of neuroligins to PSD-95.
1997,
Pubmed
Jiang,
The open pore conformation of potassium channels.
2002,
Pubmed
Jiang,
Crystal structure and mechanism of a calcium-gated potassium channel.
2002,
Pubmed
Kaneko,
Identification and characterization of novel human Ca(v)2.2 (alpha 1B) calcium channel variants lacking the synaptic protein interaction site.
2002,
Pubmed
Kay,
The importance of being proline: the interaction of proline-rich motifs in signaling proteins with their cognate domains.
2000,
Pubmed
Koradi,
MOLMOL: a program for display and analysis of macromolecular structures.
1996,
Pubmed
Kozak,
An analysis of vertebrate mRNA sequences: intimations of translational control.
1991,
Pubmed
Laskowski,
Main-chain bond lengths and bond angles in protein structures.
1993,
Pubmed
Lin,
Identification of functionally distinct isoforms of the N-type Ca2+ channel in rat sympathetic ganglia and brain.
1997,
Pubmed
,
Xenbase
Liu,
Structure of the KcsA channel intracellular gate in the open state.
2001,
Pubmed
Macias,
WW and SH3 domains, two different scaffolds to recognize proline-rich ligands.
2002,
Pubmed
Martí-Renom,
Comparative protein structure modeling of genes and genomes.
2000,
Pubmed
Niethammer,
CRIPT, a novel postsynaptic protein that binds to the third PDZ domain of PSD-95/SAP90.
1998,
Pubmed
Patil,
Preferential closed-state inactivation of neuronal calcium channels.
1998,
Pubmed
Perozo,
Structural rearrangements underlying K+-channel activation gating.
1999,
Pubmed
Pragnell,
Calcium channel beta-subunit binds to a conserved motif in the I-II cytoplasmic linker of the alpha 1-subunit.
1994,
Pubmed
Robbe,
Role of p/q-Ca2+ channels in metabotropic glutamate receptor 2/3-dependent presynaptic long-term depression at nucleus accumbens synapses.
2002,
Pubmed
Sali,
Comparative protein modelling by satisfaction of spatial restraints.
1993,
Pubmed
Shi,
Molecular determinants of voltage-dependent slow inactivation of the Ca2+ channel.
2002,
Pubmed
,
Xenbase
Stotz,
Fast inactivation of voltage-dependent calcium channels. A hinged-lid mechanism?
2000,
Pubmed
Stotz,
Identification of inactivation determinants in the domain IIS6 region of high voltage-activated calcium channels.
2001,
Pubmed
Sudol,
NeW wrinkles for an old domain.
2000,
Pubmed
Verdecia,
Structural basis for phosphoserine-proline recognition by group IV WW domains.
2000,
Pubmed
Walker,
A beta 4 isoform-specific interaction site in the carboxyl-terminal region of the voltage-dependent Ca2+ channel alpha 1A subunit.
1998,
Pubmed
Walker,
A new beta subtype-specific interaction in alpha1A subunit controls P/Q-type Ca2+ channel activation.
1999,
Pubmed
,
Xenbase
Zhang,
Citron binds to PSD-95 at glutamatergic synapses on inhibitory neurons in the hippocampus.
1999,
Pubmed
Zhang,
Molecular determinants of voltage-dependent inactivation in calcium channels.
1994,
Pubmed
,
Xenbase
Zhong,
Control of gating mode by a single amino acid residue in transmembrane segment IS3 of the N-type Ca2+ channel.
2001,
Pubmed