Functional Roles of Ca
            <sub>v</sub>
            1.3 (α
            <sub>1D</sub>
            ) Calcium Channel in Sinoatrial Nodes

Zhang, Zhao; Xu, Yancheng; Song, Haitao; Rodriguez, Jennifer; Tuteja, Dipika; Namkung, Yoon; Shin, Hee Sup; Chiamvimonvat, Nipavan

doi:10.1161/01.res.0000018003.14304.e2

Cited by 200 publications

(125 citation statements)

References 33 publications

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“…In addition, Ca v 1.3 −/− mice reproduce severe AV dysfunction typical of human congenital heart block (16). Previous studies demonstrated that Ca v 1.3-mediated I Ca,L plays a major role in the determination of heart rate and impulse conduction in mice and humans (10,11,14,16,17,19). However, despite the importance of Ca v 1.3-mediated I Ca,L in determining the rate of the diastolic depolarization in isolated SAN and AV node myocytes (14,16), it was unclear how Ca v 1.3 loss of function translates into SSS in vivo.…”

Section: Discussionmentioning

confidence: 99%

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G protein-gated I _KACh channels as therapeutic targets for treatment of sick sinus syndrome and heart block

Mesirca

Bidaud

Briec

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Dysfunction of pacemaker activity in the sinoatrial node (SAN) underlies “sick sinus” syndrome (SSS), a common clinical condition characterized by abnormally low heart rate (bradycardia). If untreated, SSS carries potentially life-threatening symptoms, such as syncope and end-stage organ hypoperfusion. The only currently available therapy for SSS consists of electronic pacemaker implantation. Mice lacking L-type Cav1.3 Ca2+ channels (Cav1.3−/−) recapitulate several symptoms of SSS in humans, including bradycardia and atrioventricular (AV) dysfunction (heart block). Here, we tested whether genetic ablation or pharmacological inhibition of the muscarinic-gated K+ channel (IKACh) could rescue SSS and heart block in Cav1.3−/− mice. We found that genetic inactivation of IKACh abolished SSS symptoms in Cav1.3−/− mice without reducing the relative degree of heart rate regulation. Rescuing of SAN and AV dysfunction could be obtained also by pharmacological inhibition of IKACh either in Cav1.3−/− mice or following selective inhibition of Cav1.3-mediated L-type Ca2+ (ICa,L) current in vivo. Ablation of IKACh prevented dysfunction of SAN pacemaker activity by allowing net inward current to flow during the diastolic depolarization phase under cholinergic activation. Our data suggest that patients affected by SSS and heart block may benefit from IKACh suppression achieved by gene therapy or selective pharmacological inhibition.

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Section: Discussionmentioning

confidence: 99%

“…In addition, severe AV dysfunction is recorded in Ca v 1.3 −/− mice to variable degrees. Typically, these mice show first-and second-degree AV block (16,17,19). Complete AV block with dissociated atrial and ventricular rhythms can also be observed in these animals.…”

Section: Significancementioning

confidence: 95%

G protein-gated I _KACh channels as therapeutic targets for treatment of sick sinus syndrome and heart block

Mesirca

Bidaud

Briec

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…To examine this, ECGs were recorded following administration of propranolol and atropine to block β-adrenergic and muscarinic receptors, respectively [28]. Following autonomic block, the R wave amplitude and P, QRS, and PR durations remained similar between mice of all three genotypes (Table 2), although compared to control recordings the administration of propranolol and atropine resulted in longer P (by ~1 ms) and QRS (~ 0.5-2 ms) components (Table 2).…”

Section: Surface Ecg Recordingsmentioning

confidence: 99%

Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals

Lopez-Santiago

Meadows

Ernst

et al. 2007

Journal of Molecular and Cellular Cardiology

127

168

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In neurons, voltage-gated sodium channel β subunits regulate the expression levels, subcellular localization, and electrophysiological properties of sodium channel α subunits. However, the contribution of β subunits to sodium channel function in heart is poorly understood. We examined the role of β1 in cardiac excitability using Scn1b null mice. Compared to wildtype mice, electrocardiograms recorded from Scn1b null mice displayed longer RR intervals and extended QT c intervals, both before and after autonomic block. In acutely dissociated ventricular myocytes, loss of β1 expression resulted in a ~1.6-fold increase in both peak and persistent sodium current while channel gating and kinetics were unaffected. Na v 1.5 expression increased in null myocytes ~1.3 fold. Action potential recordings in acutely dissociated ventricular myocytes showed slowed repolarization, supporting the extended QT c interval. Immunostaining of individual myocytes or ventricular sections revealed no discernable alterations in the localization of sodium channel α or β subunits, ankyrin B , ankyrin G , N-cadherin, or connexin-43. Together, these results suggest that β1 is critical for normal cardiac excitability and loss of β1 may be associated with a long QT phenotype.

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“…Ventricular cardiac L-type Ca 2ϩ channels are predominantly formed by the Ca v 1.2 subunit, which is also expressed at high levels in atria (5,27). Ca v 1.3 subunits, which are only expressed in atria at much lower levels than Ca v 1.2 subunits, control pacemaker activity (19,36). Whether RhoA also regulates the activity of Ca v 1.2 and Ca v 1.3 channels in atrial myocytes is worth additional investigation.…”

Section: Discussionmentioning

confidence: 99%

RhoA GTPase regulates L-type Ca²⁺currents in cardiac myocytes

Yatani¹,

Irie

Otani

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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Regulation of ionic channels plays a pivotal role in controlling cardiac function. Here we show that the Rho family of small G proteins regulates L-type Ca 2ϩ currents in ventricular cardiomyocytes. Ventricular myocytes isolated from transgenic (TG) mice that overexpress the specific GDP dissociation inhibitor Rho GDI-␣ exhibited significantly decreased basal L-type Ca 2ϩ current density (ϳ40%) compared with myocytes from nontransgenic (NTG) mice. The Ca 2ϩ channel agonist BAY K 8644 and the ␤-adrenergic agonist isoproterenol increased Ca 2ϩ currents in both NTG and TG myocytes to a similar maximal level, and no changes in mRNA or protein levels were observed in the Ca 2ϩ channel ␣1-subunits. These results suggest that the channel activity but not the expression level was altered in TG myocytes. In addition, the densities of inward rectifier and transient outward K ϩ currents were unchanged in TG myocytes. The amplitudes and rates of basal twitches and Ca 2ϩ transients were also similar between the two groups. When the protein was delivered directly into adult ventricular myocytes via TAT-mediated protein transduction, Rho GDI-␣ significantly decreased Ca 2ϩ current density, which supports the idea that the defective Ca 2ϩ channel activity in TG myocytes was a primary effect of the transgene. In addition, expression of a dominant-negative RhoA but not a dominant-negative Rac-1 or Cdc42 also significantly decreased Ca 2ϩ current density, which indicates that inhibition of Ca 2ϩ channel activity by overexpression of Rho GDI-␣ is mediated by inhibition of RhoA. This study points to the L-type Ca 2ϩ channel activity as a novel downstream target of the RhoA signaling pathway.

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Functional Roles of Ca _v 1.3 (α _1D ) Calcium Channel in Sinoatrial Nodes

Cited by 200 publications

References 33 publications

G protein-gated I _KACh channels as therapeutic targets for treatment of sick sinus syndrome and heart block

G protein-gated I _KACh channels as therapeutic targets for treatment of sick sinus syndrome and heart block

Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals

RhoA GTPase regulates L-type Ca²⁺currents in cardiac myocytes

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Functional Roles of Ca v 1.3 (α 1D ) Calcium Channel in Sinoatrial Nodes

Cited by 200 publications

References 33 publications

G protein-gated I KACh channels as therapeutic targets for treatment of sick sinus syndrome and heart block

G protein-gated I KACh channels as therapeutic targets for treatment of sick sinus syndrome and heart block

Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals

RhoA GTPase regulates L-type Ca2+currents in cardiac myocytes

Contact Info

Product

Resources

About

Functional Roles of Ca _v 1.3 (α _1D ) Calcium Channel in Sinoatrial Nodes

G protein-gated I _KACh channels as therapeutic targets for treatment of sick sinus syndrome and heart block

G protein-gated I _KACh channels as therapeutic targets for treatment of sick sinus syndrome and heart block

RhoA GTPase regulates L-type Ca²⁺currents in cardiac myocytes