Swapping the I-II intracellular linker between L-type Ca<sub>V</sub>1.2 and R-type Ca<sub>V</sub>2.3 high-voltage gated calcium channels exchanges activation attributes

González-Gutiérrez, Giovanni; Miranda-Laferte, Erick; Contreras, Gloria; Neely, Alan; Hidalgo, Patricia

doi:10.4161/chan.4.1.10562

Cited by 9 publications

(8 citation statements)

References 40 publications

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“…As observed in the GV relations of our channel chimeras, our data exhibits similar trends with mutations that increase the PL helical propensity or the effect of Ca V ␤ binding, i.e., a leftward shift. Similar trends were observed in a recent report where the first 70 I-II linker residues were interchanged between Ca V 1.2 and Ca V 2.3 (Gonzalez-Gutierrez et al, 2010). Nonetheless, the persistent effects of the PL mutations in the absence of Ca V ␤ indicate that this region, independent of the binding of Ca V ␤, has helical secondary structure rather than random coil.…”

Section: Discussionsupporting

confidence: 87%

The Role of a Voltage-Dependent Ca²⁺Channel Intracellular Linker: A Structure-Function Analysis

et al. 2012

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Voltage-dependent calcium channels (VDCCs) allow the passage of Ca 2ϩ ions through cellular membranes in response to membrane depolarization. The channel pore-forming subunit, ␣1, and a regulatory subunit (Ca V ␤) form a high affinity complex where Ca V ␤ binds to a ␣1 interacting domain in the intracellular linker between ␣1 membrane domains I and II (I-II linker). We determined crystal structures of Ca V ␤2 functional core in complex with the Ca V 1.2 and Ca V 2.2 I-II linkers to a resolution of 1.95 and 2.0 Å, respectively. Structural differences between the highly conserved linkers, important for coupling Ca V ␤ to the channel pore, guided mechanistic functional studies. Electrophysiological measurements point to the importance of differing linker structure in both Ca V 1 and 2 subtypes with mutations affecting both voltage-and calcium-dependent inactivation and voltage dependence of activation. These linker effects persist in the absence of Ca V ␤, pointing to the intrinsic role of the linker in VDCC function and suggesting that I-II linker structure can serve as a brake during inactivation.

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Section: Discussionsupporting

confidence: 87%

The Role of a Voltage-Dependent Ca²⁺Channel Intracellular Linker: A Structure-Function Analysis

et al. 2012

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“…Structure-function studies have shown that β binding at the alpha interaction domain (AID) of I-II loop induces a coil-to-helix conformation of the proximal linker, strengthening the connection between the pore and the β subunit/I-II loop complex (Opatowsky et al, 2004;Van Petegem et al, 2004;Arias et al, 2005;Findeisen and Minor, 2009;Almagor et al, 2012). Proximal linker structure integrity is thought to be essential for β-dependent modulation of α 1 gating but its role in the localization of the channel has been less investigated (Findeisen and Minor, 2009;Gonzalez-Gutierrez et al, 2010;Almagor et al, 2012). So according to these data, the n2368 mutation in IS6 could possibly disrupt the proximal linker integrity, decreasing β modulation of channel inactivation and α 1 trafficking.…”

Section: Research Articlementioning

confidence: 99%

Hyperactivation of L-type voltage-gated Ca2+ channels in C. elegans striated muscle can result from point mutations in the IS6 or the IIIS4 segment of the α1 subunit.

Lainé

Ségor

Zhan

et al. 2014

Journal of Experimental Biology

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Several human diseases, including hypokalemic periodic paralysis and Timothy syndrome, are caused by mutations in voltage-gated calcium channels. The effects of these mutations are not always well understood, partially because of difficulties in expressing these channels in heterologous systems. The use of Caenorhabditis elegans could be an alternative approach to determine the effects of mutations on voltage-gated calcium channel function because all the main types of voltage-gated calcium channels are found in C. elegans, a large panel of mutations already exists and efficient genetic tools are available to engineer customized mutations in any gene. In this study, we characterize the effects of two gain-of-function mutations in egl-19, which encodes the L-type calcium channel α 1 subunit. One of these mutations, ad695, leads to the replacement of a hydrophobic residue in the IIIS4 segment. The other mutation, n2368, changes a conserved glycine of IS6 segment; this mutation has been identified in patients with Timothy syndrome. We show that both egl-19 (gain-of-function) mutants have defects in locomotion and morphology that are linked to higher muscle tone. Using in situ electrophysiological approaches in striated muscle cells, we provide evidence that this high muscle tone is due to a shift of the voltage dependency towards negative potentials, associated with a decrease of the inactivation rate of the L-type Ca 2+ current. Moreover, we show that the maximal conductance of the Ca 2+ current is decreased in the strongest mutant egl-19(n2368), and that this decrease is correlated with a mislocalization of the channel.

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“…All β-subunit variants, except for the short splice forms β 4c (Hibino et al, 2003) and β 1d , (Cohen et al, 2005) and a few others found in the heart (Foell et al, 2004), share this architecture (Figure 3). Association of the β-subunit with the AID site induces a coil-to-helix transition in the AID region that likely extends to the S6 segment of the first repeat (Findeisen and Minor, 2009; Gonzalez-Gutierrez et al, 2010). Although a clear mechanism of how the β-subunit facilitates pore opening or forward trafficking of the channel was not readily deducible from the three-dimensional structures, these studies opened up new scenarios to explain β-modulation.…”

Section: Beta Subunitmentioning

confidence: 99%

“…Since cytoplasmic loops start as an extension of the sixth segment of each repeat, they are likely to influence channel gating. We swapped the I–II loop of the poorly coupled Ca V 1.2 channel with the efficiently coupled Ca V 2.3 and found that these phenotypes were transferred independently of β-subunit interaction (Gonzalez-Gutierrez et al, 2010). When the β-subunit is present, the coupling efficiency is sensitive to the residues within the AID domain that are exposed to the milieu (Gonzalez-Gutierrez et al, 2008a).…”

Section: Beta Subunitmentioning

confidence: 99%

Structure-function of proteins interacting with the Î±1 pore-forming subunit of high-voltage-activated calcium channels

Neely

Hidalgo

2014

Front. Physiol.

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Openings of high-voltage-activated (HVA) calcium channels lead to a transient increase in calcium concentration that in turn activate a plethora of cellular functions, including muscle contraction, secretion and gene transcription. To coordinate all these responses calcium channels form supramolecular assemblies containing effectors and regulatory proteins that couple calcium influx to the downstream signal cascades and to feedback elements. According to the original biochemical characterization of skeletal muscle Dihydropyridine receptors, HVA calcium channels are multi-subunit protein complexes consisting of a pore-forming subunit (α1) associated with four additional polypeptide chains β, α2, δ, and γ, often referred to as accessory subunits. Twenty-five years after the first purification of a high-voltage calcium channel, the concept of a flexible stoichiometry to expand the repertoire of mechanisms that regulate calcium channel influx has emerged. Several other proteins have been identified that associate directly with the α1-subunit, including calmodulin and multiple members of the small and large GTPase family. Some of these proteins only interact with a subset of α1-subunits and during specific stages of biogenesis. More strikingly, most of the α1-subunit interacting proteins, such as the β-subunit and small GTPases, regulate both gating and trafficking through a variety of mechanisms. Modulation of channel activity covers almost all biophysical properties of the channel. Likewise, regulation of the number of channels in the plasma membrane is performed by altering the release of the α1-subunit from the endoplasmic reticulum, by reducing its degradation or enhancing its recycling back to the cell surface. In this review, we discuss the structural basis, interplay and functional role of selected proteins that interact with the central pore-forming subunit of HVA calcium channels.

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Swapping the I-II intracellular linker between L-type Ca_V1.2 and R-type Ca_V2.3 high-voltage gated calcium channels exchanges activation attributes

Abstract: (2010) Swapping the I-II intracellular linker between L-type Ca V 1.2 and Rtype Ca V 2.3 high-voltage gated calcium channels exchanges activation attributes, Channels, 4:1, 42-50,

Cited by 9 publications

References 40 publications

The Role of a Voltage-Dependent Ca²⁺Channel Intracellular Linker: A Structure-Function Analysis

The Role of a Voltage-Dependent Ca²⁺Channel Intracellular Linker: A Structure-Function Analysis

Hyperactivation of L-type voltage-gated Ca2+ channels in C. elegans striated muscle can result from point mutations in the IS6 or the IIIS4 segment of the α1 subunit.

Structure-function of proteins interacting with the Î±1 pore-forming subunit of high-voltage-activated calcium channels

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Swapping the I-II intracellular linker between L-type CaV1.2 and R-type CaV2.3 high-voltage gated calcium channels exchanges activation attributes

Abstract: (2010) Swapping the I-II intracellular linker between L-type Ca V 1.2 and Rtype Ca V 2.3 high-voltage gated calcium channels exchanges activation attributes, Channels, 4:1, 42-50,

Cited by 9 publications

References 40 publications

The Role of a Voltage-Dependent Ca2+Channel Intracellular Linker: A Structure-Function Analysis

The Role of a Voltage-Dependent Ca2+Channel Intracellular Linker: A Structure-Function Analysis

Hyperactivation of L-type voltage-gated Ca2+ channels in C. elegans striated muscle can result from point mutations in the IS6 or the IIIS4 segment of the α1 subunit.

Structure-function of proteins interacting with the Î±1 pore-forming subunit of high-voltage-activated calcium channels

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Swapping the I-II intracellular linker between L-type Ca_V1.2 and R-type Ca_V2.3 high-voltage gated calcium channels exchanges activation attributes

The Role of a Voltage-Dependent Ca²⁺Channel Intracellular Linker: A Structure-Function Analysis

The Role of a Voltage-Dependent Ca²⁺Channel Intracellular Linker: A Structure-Function Analysis