RGD Reference Report - Interaction via a key tryptophan in the I-II linker of N-type calcium channels is required for beta1 but not for palmitoylated beta2, implicating an additional binding site in the regulation of channel voltage-dependent properties.

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Interaction via a key tryptophan in the I-II linker of N-type calcium channels is required for beta1 but not for palmitoylated beta2, implicating an additional binding site in the regulation of channel voltage-dependent properties.
Authors:	Leroy, J Richards, MW Butcher, AJ Nieto-Rostro, M Pratt, WS Davies, A Dolphin, AC
Citation:	Leroy J, etal., J Neurosci. 2005 Jul 27;25(30):6984-96.
RGD ID:	8553837
Pubmed:	PMID:16049174 (View Abstract at PubMed)
PMCID:	PMC6724838 (View Article at PubMed Central)
DOI:	DOI:10.1523/JNEUROSCI.1137-05.2005 (Journal Full-text)
The CaVbeta subunits of voltage-gated calcium channels regulate these channels in several ways. Here we investigate the role of these auxiliary subunits in the expression of functional N-type channels at the plasma membrane and in the modulation by G-protein-coupled receptors of this neuronal channel. To do so, we mutated tryptophan 391 to an alanine within the alpha-interacting domain (AID) in the I-II linker of CaV2.2. We showed that the mutation W391 virtually abolishes the binding of CaVbeta1b and CaVbeta2a to the CaV2.2 I-II linker and strongly reduced current density and cell surface expression of both CaV2.2/alpha2delta-2/beta1b and/beta2a channels. When associated with CaVbeta1b, the W391A mutation also prevented the CaVbeta1b-mediated hyperpolarization of CaV2.2 channel activation and steady-state inactivation. However, the mutated CaV2.2W391A/beta1b channels were still inhibited to a similar extent by activation of the D2 dopamine receptor with the agonist quinpirole. Nevertheless, key hallmarks of G-protein modulation of N-type currents, such as slowed activation kinetics and prepulse facilitation, were not observed for the mutated channel. In contrast, CaVbeta2a was still able to completely modulate the biophysical properties of CaV2.2W391A channel and allow voltage-dependent G-protein modulation of CaV2.2W391A. Additional data suggest that the concentration of CaVbeta2a in the proximity of the channel is enhanced independently of its binding to the AID by its palmitoylation. This is essentially sufficient for all of the functional effects of CaVbeta2a, which may occur via a second lower-affinity binding site, except trafficking the channel to the plasma membrane, which requires interaction with the AID region.

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Cacnb1	Rat	protein binding	enables	IPI	UniProtKB:Q05152	PMID:16049174	UniProt
Cacnb3	Rat	protein binding	enables	IPI	UniProtKB:Q05152	PMID:16049174	UniProt

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Genes (Rattus norvegicus)

Cacnb1 (calcium voltage-gated channel auxiliary subunit beta 1)

Cacnb3 (calcium voltage-gated channel auxiliary subunit beta 3)

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Interaction via a key tryptophan in the I-II linker of N-type calcium channels is required for beta1 but not for palmitoylated beta2, implicating an additional binding site in the regulation of channel voltage-dependent properties.