Facilitation and Ca2+-dependent Inactivation Are Modified by Mutation of the Cav1.2 Channel IQ Motif

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confidence: 99%

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confidence: 99%

Mutation of the Calmodulin Binding Motif IQ of the L-type Cav1.2 Ca2+ Channel to EQ Induces Dilated Cardiomyopathy and Death

Blaich

Pahlavan

Tian

et al. 2012

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“…Voltage-dependent facilitation of the channel requires in vitro and in vivo the CaM-KII dependent phosphorylation of Ser-1512 and Ser-1570 (16, 17). In addition, binding of CaM to the IQ motif located in the CCt is essential for Ca 2ϩ -dependent inhibition and facilitation of the channel (8,10,18,19).The distal CCt of the Ca V 1.2 channel (amino acids 1642-2143) has been reported to translocate to the nucleus and to modulate the transcription of several genes (20). Cleavage of the channel at residue 1623 does not result in a functional channel protein (21).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Truncation of Murine Cav1.2 at Asp-1904 Results in Heart Failure after Birth

Domes

Ding

Lemke

et al. 2011

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The cardiac Ca V 1.2 calcium channel, a dihydropyridine-sensitive L-type channel, is widely expressed and is of functional importance for neurons, the cardiac myocytes (CMs), 2 and vascular and intestinal smooth muscle (1). Global and heart specific deletion of the Ca V 1.2 gene is embryonically lethal (2). Smooth muscle-specific deletion of the Ca V 1.2 channel leads to defects in blood pressure regulation (3), intestinal dysfunction (4), and death (5). In contrast to the cardiovascular system, deletion of the Ca V 1.2 channel in the CNS does not affect survival. However, its specific deletion affects learning processes in the hippocampus and in the lateral amygdala (6, 7).Voltage-dependent opening of the Ca V 1.2 channel facilitates greatly Ca 2ϩ entry into CMs and triggers thereby opening of ryanodine receptors to initiate muscle contraction. Two mechanisms allow closing of the channel, namely a Ca 2ϩ -and a voltage-dependent process. Ca 2ϩ -dependent inactivation is mediated by the carboxyl terminus of the channel (CCt). There is excellent evidence that modifications at the CCt affect significantly the inactivation of the channel (8 -15). Cardiac Ca V 1.2 channels are modulated by CaM and CaM kinase II (CaM-KII). Voltage-dependent facilitation of the channel requires in vitro and in vivo the CaM-KII dependent phosphorylation of Ser-1512 and Ser-1570 (16, 17). In addition, binding of CaM to the IQ motif located in the CCt is essential for Ca 2ϩ -dependent inhibition and facilitation of the channel (8,10,18,19).The distal CCt of the Ca V 1.2 channel (amino acids 1642-2143) has been reported to translocate to the nucleus and to modulate the transcription of several genes (20). Cleavage of the channel at residue 1623 does not result in a functional channel protein (21). However, proteolytic cleavage of the channel at residue 1821 (22) yields a functional channel and an inhibitory molecule of 35 kDa (23). At present it is not clear, if the proteolytic processing of the C terminus of Ca V 1.2 is a regulated or tonic event and which processes control translocation of CCt to the nucleus. Nuclear location increased with low cytosolic [Ca 2ϩ ] and decreased with increasing cytosolic [Ca 2ϩ ], i.e. with activation of the truncated Ca V 1.2 channel (20). In neurons, the CCt regulates the expression of a number of genes (20), whereas in CMs, the truncated CCt (amino acids 1906 -2171) caused an 80% decrease of the Ca V 1.2 promoter activity (23). Furthermore, proteolysis of the Ca V 1.2 protein appears to be important to observe cAMP kinase-dependent regulation of the channel (15). In tsA-201 cells, coexpression of a rabbit Ca V 1.2a-1800stop channel together with the proteolytically derived CCt of the Ca V 1.2 was essential to observe a cAMP kinase-induced positive inotropic effect (15). On the other hand, a cAMP kinase-dependent regulation of the Ca V 1.2a channel was reported, when a Ca V 1.2-1905stop construct was expressed in HEK293 cells together with the Ca V ␤2 subunit (24) but not when co-expressed in guinea ...

“…Facilitation of I Ca was measured as described in Ref. 30. The stimulatory effect of isoproterenol (100 nmol/liter containing an equal concentration of ascorbic acid) on I Ca was examined after establishing a solid base line.…”

Section: Methodsmentioning

confidence: 99%

Deletion of the C-terminal Phosphorylation Sites in the Cardiac β-Subunit Does Not Affect the Basic β-Adrenergic Response of the Heart and the Cav1.2 Channel

Brandmayr

Poomvanicha

Domes

et al. 2012

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Background: ␤-Adrenergic receptors stimulate cardiac I Ca via PKA-dependent phosphorylation. Results: Deletion of the C-terminal phosphorylation sites in the ␤ 2 gene did not affect isoproterenol-stimulated I Ca . Conclusion: Phosphorylation of the C terminus of the ␤ 2 subunit in vivo does not contribute to ␤-adrenergic regulation of I Ca . Significance: The PKA-dependent regulation of I Ca does not require the C terminus of the ␤ 2 subunit.