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Fan, Qigao; Vanderpool, Kathleen M.; O’Connor, Jessica; Marsh, James D.

doi:10.1023/a:1021128017974

Cited by 4 publications

(3 citation statements)

References 36 publications

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“…21,22 The Ca v β subunits co-assemble with pore-forming α-subunits during channel biogenesis to promote the trafficking of the Ca 2+ channel complex from the ER to the PM. 14,19 Although Ca v β are postulated to mask an ER retention signal in α-subunits as a mechanism to target Ca 2+ channels to the cell surface, no specific motif has been identified.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, Fan et al 22 designed mutant Ca v β subunits that interact with α 1C intracellularly, but lack the motifs required to target the Ca v 1.2 channel complex to the PM. These β subunit “decoys” represent potential therapeutics to reduce Ca v 1.2 surface expression in cardiovascular pathologies characterized by an overabundance of Ca v 1.2 channels.…”

Section: Discussionmentioning

confidence: 99%

“…These β subunit “decoys” represent potential therapeutics to reduce Ca v 1.2 surface expression in cardiovascular pathologies characterized by an overabundance of Ca v 1.2 channels. 22,27,28 It may be advantageous to ameliorate anomalous Ca 2+ influx by preventing the upregulation of Ca v 1.2 channels rather than using pharmacological blockers to reduce the activity of over-expressed channels. Our findings provide proof-of-principle for this concept by showing that Ca v β3 deletion can normalize Ca v 1.2 channel expression in VSMCs of hypertensive mice in which Ca v 1.2 over-expression is a contributing defect.…”

Section: Discussionmentioning

confidence: 99%

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The β3 Subunit Contributes to Vascular Calcium Channel Upregulation and Hypertension in Angiotensin II–Infused C57BL/6 Mice

et al. 2013

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Voltage-gated L-type Ca2+ (Cav1.2) channels in vascular smooth muscle cells (VSMCs) are a predominant Ca2+ influx pathway that mediates arterial tone. Channel biogenesis is accomplished when the pore-forming α1C subunit co-assembles with regulatory Cavβ subunits intracellularly, and the multi-protein Cav1.2 complex translocates to the plasma membrane to form functional Ca2+ channels. We hypothesized that the main Cavβ isoform in VSMCs, Cavβ3, is required for the upregulation of arterial Cav1.2 channels during the development of hypertension, an event associated with abnormal Ca2+-dependent tone. Cav1.2 channel expression and function was compared between 2nd order mesenteric arteries (MA) of C57BL/6 wild-type (WT) and Cavβ3-/- mice infused with saline (control) or angiotensin II (Ang II) for 2 weeks to induce hypertension. The MA of Ang II-infused WT mice showed increased Cav1.2 channel expression and accentuated Ca2+-mediated contractions compared to saline-infused WT mice. In contrast, Cav1.2 channels failed to upregulate in MA of Ang II-infused Cavβ3-/- mice and Ca2+-dependent reactivity was normal in these arteries. Basal systolic blood pressure (SBP) was not significantly different between WT and Cavβ3-/- mice (98±2 mm Hg and 102±3 mm Hg, respectively), but the Cavβ3-/- mice showed a blunted pressor response to Ang II infusion. Two weeks after the start of Ang II administration, the SBP of Cavβ3-/- mice averaged 149±4 mm Hg compared to 180±5 mm Hg in WT mice. Thus, the Cavβ3 subunit is a critical regulatory protein required to upregulate arterial Cav1.2 channels and fully develop angiotensin II –dependent hypertension in C57BL/6 mice.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The β3 Subunit Contributes to Vascular Calcium Channel Upregulation and Hypertension in Angiotensin II–Infused C57BL/6 Mice

et al. 2013

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Vascular calcium channels and high blood pressure: Pathophysiology and therapeutic implications

Sonkusare

Palade

Marsh

et al. 2006

Vascular Pharmacology

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115

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Long-lasting Ca 2+ (Ca L ) channels of the Ca v 1.2 gene family are heteromultimeric structures that are minimally composed of a pore-forming α 1C subunit and regulatory β and α 2 δ subunits in vascular smooth muscle cells. The Ca L channels are the primary pathways for voltage-gated Ca 2+ influx that trigger excitation-contraction coupling in small resistance vessels. Notably, vascular smooth muscle cells of hypertensive rats show an increased expression of Ca L channel α 1C subunits, which is associated with elevated Ca 2+ influx and the development of abnormal arterial tone. Indeed, blood pressure per se appears to promote Ca L channel expression in small arteries, and even short-term rises in pressure may alter channel expression. Membrane depolarization has been shown to be one stimulus associated with elevated blood pressure that promotes Ca L channel expression at the plasma membrane. Future studies to define the molecular processes that regulate Ca L channel expression in vascular smooth muscle cells will provide a rational basis for designing antihypertensive therapies to normalize Ca L channel expression and the development of anomalous vascular tone in hypertensive pathologies.

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Design of Mutant β₂Subunits as Decoy Molecules to Reduce the Expression of Functional Ca²⁺Channels in Cardiac Cells

Télémaque

Sonkusare²,

Grain³

et al. 2008

J Pharmacol Exp Ther

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Calcium influx through long-lasting ("L-type") Ca 2ϩ channels (Ca V ) drives excitation-contraction in the normal heart. Dysregulation of this process contributes to Ca 2ϩ overload, and interventions that reduce expression of the pore-forming ␣ 1 subunit may alleviate cytosolic Ca 2ϩ excess. As a molecular approach to disrupt the assembly of Ca V 1.2 (␣ 1C ) channels at the cell membrane, we targeted the Ca 2ϩ channel ␤ 2 subunit, an intracellular chaperone that interacts with ␣ 1C via its ␤ interaction domain (BID) to promote Ca V 1.2 channel expression. Recombinant adenovirus expressing either the full ␤ 2 subunit (Full-␤ 2 ) or truncated ␤ 2 subunit constructs lacking either the C terminus, N terminus, or both (N-BID, C-BID, and BID, respectively) fused to green fluorescent protein were developed as potential decoys and overexpressed in HL-1 cells. Fluorescence microscopy revealed that the localization of Full-␤ 2 at the surface membrane was associated with increased Ca 2ϩ current mainly attributed to Ca V 1.2 channels. In contrast, truncated N-BID and C-BID constructs showed punctate intracellular expression, and BID showed a diffuse cytosolic distribution. Total expression of the ␣ 1C protein of Ca V 1.2 channels was similar between groups, but HL-1 cells overexpressing C-BID and BID exhibited reduced Ca 2ϩ current. C-BID and BID also attenuated Ca 2ϩ current associated with another L-type Ca 2ϩ channel, Ca V 1.3, but they did not reduce transient Ca 2ϩ currents attributed to Ca V 3 channels. These results suggest that ␤ 2 subunit mutants lacking the N terminus may preferentially disrupt the proper localization of L-type Ca 2ϩ channels in the cell membrane. Cardiac-specific delivery of these decoy molecules in vivo may represent a gene-based treatment for pathologies involving Ca 2ϩ overload.The predominant voltage-gated Ca 2ϩ channels (Ca V ) in cardiac cells are the dihydropyridine-sensitive Ca V 1.2 (␣ 1C ) channels that mediate long-lasting ("L-type") Ca 2ϩ current as a critical step in excitation-contraction coupling (Bers, 2002). The Ca V 1.2 channels are multiprotein complexes composed of a large, pore-forming ␣ 1C subunit and accessory ␤ and ␣ 2 -␦ subunits. The expression level of functional Ca V 1.2 channels is regulated by the ␤ subunits (␤ 1 , ␤ 2 , ␤ 3 , and ␤ 4 ), which are cytoplasmic proteins encoded by four different genes, including multiple splice variants (Foell et al., 2004). The ␤ 2 subunit is predominantly expressed in rat ventricular myocytes, although other gene families have been reported. It is noteworthy that ␤ 2 acts as a molecular chaperone that escorts ␣ 1C to the sarcolemma to localize functional Ca V 1.2 channels at the surface membrane De Waard et al., 1996;Opatowsky et al., 2003). Indeed, we recently reported that overexpression of ␤ 2 in isolated feline ventricular myocytes significantly increases Ca 2ϩ influx and cardiac contractility (Chen et al., 2005). Although mutations This work was supported in part by the

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Cited by 4 publications

References 36 publications

The β3 Subunit Contributes to Vascular Calcium Channel Upregulation and Hypertension in Angiotensin II–Infused C57BL/6 Mice

The β3 Subunit Contributes to Vascular Calcium Channel Upregulation and Hypertension in Angiotensin II–Infused C57BL/6 Mice

Vascular calcium channels and high blood pressure: Pathophysiology and therapeutic implications

Design of Mutant β₂Subunits as Decoy Molecules to Reduce the Expression of Functional Ca²⁺Channels in Cardiac Cells

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Cited by 4 publications

References 36 publications

The β3 Subunit Contributes to Vascular Calcium Channel Upregulation and Hypertension in Angiotensin II–Infused C57BL/6 Mice

The β3 Subunit Contributes to Vascular Calcium Channel Upregulation and Hypertension in Angiotensin II–Infused C57BL/6 Mice

Vascular calcium channels and high blood pressure: Pathophysiology and therapeutic implications

Design of Mutant β2Subunits as Decoy Molecules to Reduce the Expression of Functional Ca2+Channels in Cardiac Cells

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Design of Mutant β₂Subunits as Decoy Molecules to Reduce the Expression of Functional Ca²⁺Channels in Cardiac Cells