Complex modulation of L-type Ca2+ current inactivation by sorcin in isolated rabbit cardiomyocytes

Fowler, Mark R.; Colotti, Gianni; Chiancone, Emilia; Higuchi, Yoshiharu; Seidler, Tim; Smith, Godfrey L.

doi:10.1007/s00424-008-0575-5

Cited by 28 publications

(23 citation statements)

References 34 publications

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“…Our unbiased analysis of transcriptional changes after mutation of single miR-1/133a clusters revealed the miR-1 target Sorcin [36] to be significantly upregulated at least in miR-1-1/133a-2 knock-out mice and we could confirm this finding at the protein level. Whereas it is established that Sorcin may enhance contractility of cardiomyocytes, it is currently unclear whether Sorcin might also modulate L-type calcium channel activity in vivo [37]. We found moderate upregulation of Sorcin only in one of the models.…”

Section: Discussioncontrasting

confidence: 48%

MiRNA-1/133a Clusters Regulate Adrenergic Control of Cardiac Repolarization

et al. 2014

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The electrical properties of the heart are primarily determined by the activity of ion channels and the activity of these molecules is permanently modulated and adjusted to the physiological needs by adrenergic signaling. miRNAs are known to control the expression of many proteins and to fulfill distinct functions in the mammalian heart, though the in vivo effects of miRNAs on the electrical activity of the heart are poorly characterized. The miRNAs miR-1 and miR-133a are the most abundant miRNAs of the heart and are expressed from two miR-1/133a genomic clusters. Genetic modulation of miR-1/133a cluster expression without concomitant severe disturbance of general cardiomyocyte physiology revealed that these miRNA clusters govern cardiac muscle repolarization. Reduction of miR-1/133a dosage induced a longQT phenotype in mice especially at low heart rates. Longer action potentials in cardiomyocytes are caused by modulation of the impact of β-adrenergic signaling on the activity of the depolarizing L-type calcium channel. Pharmacological intervention to attenuate β-adrenergic signaling or L-type calcium channel activity in vivo abrogated the longQT phenotype that is caused by modulation of miR-1/133a activity. Thus, we identify the miR-1/133a miRNA clusters to be important to prevent a longQT-phenotype in the mammalian heart.

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Section: Discussioncontrasting

confidence: 48%

MiRNA-1/133a Clusters Regulate Adrenergic Control of Cardiac Repolarization

et al. 2014

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“…As previously described [16], a partial rabbit sorcin sequence was amplified using primers based on the known human sorcin sequence by reverse transcription of RNA from a chinchilla bastard rabbit. Sense and antisense oligonucleotides were chosen to target the 19 nucleotide segment complementary to the rabbit sorcin mRNA sequence GCAAGAUCACCUUCGAUGA and ligated downstream of a U6 promoter into vector pSIREN-DNR (BD Biosciences Clontec, Palo Alto, USA).…”

Section: Methodsmentioning

confidence: 99%

Activation of the cardiac Na+–Ca2+ exchanger by sorcin via the interaction of the respective Ca2+-binding domains

Zamparelli

Macquaide

Colotti

et al. 2010

Journal of Molecular and Cellular Cardiology

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Sorcin is a penta-EF-hand protein that interacts with intracellular target proteins after Ca2+ binding. The sarcolemmal Na+/Ca2+ exchanger (NCX1) may be an important sorcin target in cardiac muscle. In this study, RNAi knockdown of sorcin, purified sorcin or sorcin variants was employed in parallel measurements of: (i) NCX activity in isolated rabbit cardiomyocytes using electrophysiological techniques and (ii) sorcin binding to the NCX1 calcium binding domains (CBD1 and (iii) using surface plasmon resonance and gel overlay techniques. Sorcin is activated by Ca2+ binding to the EF3 and EF2 regions, which are connected by the D helix. To investigate the importance of this region in the interaction with NCX1, three variants were examined: W105G and W99G, mutated respectively near EF3 and EF2, and E124A that does not bind Ca2+ due to a mutation at EF3. Downregulation of sorcin decreased and supplementation with wt sorcin (3 μM) increased NCX activity in isolated cardiomyocytes. The relative stimulatory effects of the sorcin variants were: W105G > wt sorcin > Sorcin Calcium Binding Domain (SCBD) > W99G > E124A. Sorcin binding to both CBD1 and 2 was observed. In the presence of 50 µM Ca2+, the interaction with CBD1 followed the order W105G > SCBD > wt sorcin > W99G > E124A. In sorcin, the interacting surface can be mapped on the C-terminal Ca2+-binding domain in the D helix region comprising W99. The fast association/dissociation rates that characterize the interaction of sorcin with CBD1 and 2 may permit complex formation/dissociation during an excitation/contraction cycle.

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“…On the other hand, CDI is reduced by CaBP1, which would enhance Ca 2ϩ entry (6). Dual opposite regulation of VDI and CDI resembles the effect of sorcin (8) and may be physiologically relevant. For Ca V 1.2 channels in ventricular cardiomyocytes, VDI may primarily regulate channel function under basal conditions, whereas CDI is dominant upon ␤-adrenergic stimulation (51,52).…”

Section: Discussionmentioning

confidence: 99%

CaBP1 Regulates Voltage-dependent Inactivation and Activation of CaV1.2 (L-type) Calcium Channels

Tsemakhovich

Christel

et al. 2011

Journal of Biological Chemistry

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CaBP1 is a CaCaBP1 is a Ca 2ϩ -binding protein enriched in the brain and retina (2). It has emerged as a prominent regulator of Ca V channel CDI (4). The molecular determinants underlying CaBP1 regulation have been most well characterized for Ca V 1.2 (␣ 1C ) channels, which play crucial roles in Ca 2ϩ signaling and excitability in the nervous and cardiovascular systems (14). In contrast to Ca 2ϩ /CaM, which stabilizes the inactivated state of Ca V 1.2 (24 -26), CaBP1 fully eliminates CDI and supports Ca 2ϩ -dependent facilitation (6, 27). CaBP1 binds to the C-terminal CaM-binding ␣ 1C sites but also interacts with the ␣ 1C N-terminal domain, the deletion of which blunts the effect of CaBP1 on CDI (28). The N terminus of ␣ 1C regulates several aspects of channel gating as well as modulation by protein kinase C (29 -32). Within the N terminus, two modular segments are involved in CaM binding (33, 34) and regulation of P o (35). A "long N-terminal" alternatively spliced ␣ 1C isoform possesses a 20-amino acid (aa) initial segment (N-terminal inhibitory (NTI) module), which controls the channel's maximal P o (30,35). A second module in the central part of the N-terminal domain is a CaM-binding site, the N-terminal spatial Ca 2ϩ -transforming element (NSCaTE), which regulates CDI in Ca V 1.3 (33), but its role in Ca V 1.2 is less clear (34). The exact location of the CaBP1-binding site within the N terminus of ␣ 1C has not been determined, and whether CaBP1 influences parameters of Ca V 1.2 function other than CDI is unknown.Here, we report that CaBP1 expression in Xenopus oocytes regulates activation gating and accelerates VDI of Ca V 1.2. Although CaBP1 binds to a site in the distal N-terminal domain that is distinct from the CaM-binding site, CaBP1 regulation of VDI requires an intact proximal domain in the N terminus of ␣ 1C . Deletion of the entire N-terminal domain inhibits but does not fully abolish effects of CaBP1 on VDI, which indicates the presence of additional relevant molecular determinants. These results suggest a new modulatory role for the ␣ 1C N terminus, in which CaBP1 binding and transduction of the modulation of VDI are encoded by distinct N-terminal domains.

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Complex modulation of L-type Ca2+ current inactivation by sorcin in isolated rabbit cardiomyocytes

Cited by 28 publications

References 34 publications

MiRNA-1/133a Clusters Regulate Adrenergic Control of Cardiac Repolarization

MiRNA-1/133a Clusters Regulate Adrenergic Control of Cardiac Repolarization

Activation of the cardiac Na+–Ca2+ exchanger by sorcin via the interaction of the respective Ca2+-binding domains

CaBP1 Regulates Voltage-dependent Inactivation and Activation of CaV1.2 (L-type) Calcium Channels

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