Increasing T‐type calcium channel activity by β‐adrenergic stimulation contributes to β‐adrenergic regulation of heart rates

Abstract

Cav3.1 T-type Ca channel current (I ) contributes to heart rate genesis but is not known to contribute to heart rate regulation by the sympathetic/β-adrenergic system (SAS). We show that the loss of Cav3.1 makes the beating rates of the heart in vivo and perfused hearts ex vivo, as well as sinoatrial node cells, less sensitive to β-adrenergic stimulation; it also renders less conduction acceleration through the atrioventricular node by β-adrenergic stimulation. Increasing Cav3.1 in cardiomyocytes has the opposite effects. I in sinoatrial nodal cells can be upregulated by β-adrenergic stimulation. The results of the present study add a new contribution to heart rate regulation by the SAS system and provide potential new mechanisms for the dysregulation of heart rate and conduction by the SAS in the heart. T-type Ca channel can be a target for heart disease treatments that aim to slow down the heart rate ABSTRACT: Cav3.1 (α ) T-type Ca channel (TTCC) is expressed in mouse sinoatrial node cells (SANCs) and atrioventricular (AV) nodal cells and contributes to heart rate (HR) genesis and AV conduction. However, its role in HR regulation and AV conduction acceleration by the β-adrenergic system (SAS) is unclear. In the present study, L- (I ) and T-type (I ) Ca currents were recorded in SANCs from Cav3.1 transgenic (TG) and knockout (KO), and control mice. I was absent in KO SANCs but enhanced in TG SANCs. In anaesthetized animals, different doses of isoproterenol (ISO) were infused via the jugular vein and the HR was recorded. The EC of the HR response to ISO was lower in TG mice but higher in KO mice, and the maximal percentage of HR increase by ISO was greater in TG mice but less in KO mice. In Langendorff-perfused hearts, ISO increased HR and shortened PR intervals to a greater extent in TG but to a less extent in KO hearts. KO SANCs had significantly slower spontaneous beating rates than control SANCs before and after ISO; TG SANCs had similar basal beating rates as control SANCs probably as a result of decreased I but a greater response to ISO than control SANCs. I in SANCs was significantly increased by ISO. I upregulation by β-adrenergic stimulation contributes to HR and conduction regulation by the SAS. TTCC can be a target for slowing the HR.

Autonomic cardiac regulation facilitates acute heat tolerance in rainbow trout:in situandin vivosupport

“…While this hypothesis will require further investigation, both T-type Ca 2+ channels and the NCX are active in atrial and ventricular myocytes in some fish (Alday et al, 2014;Nemtsas et al, 2010;Vornanen, 2017). Furthermore, Ca 2+ influx through NCX is enhanced with β-adrenergic stimulation in zebrafish (Xie et al, 2008), and in mammals, β-adrenergic stimulation enhances Ca 2+ influx through both NCX and T-type Ca 2+ channels, which contributes to cardiac excitation (Herrmann et al, 2013;Kaese et al, 2017;Li et al, 2012Li et al, , 2018. Alternatively, Ca 2+ kinetics may limit the ability of the ventricle to keep up with the pacemaker rate and an imbalance in I Na and I K1 may not be to blame.…”

Concomitant genetic ablation of L-type Cav1.3 (α1D) and T-type Cav3.1 (α1G) Ca2+ channels disrupts heart automaticity

“…In addition, we have showed that Ca v 1.3 channels contribute to the generation of diastolic LCRs and are necessary to synchronize LCRs events under β-adrenergic activation of pacemaking 27 . T-type Ca v 3.1 channels have also been shown to contribute to automaticity in the SAN 24,28 and in the AVN 25 . Importantly, loss-of-function of Ca v 1.3 and Ca v 3.1 channels underlies congenital 29 and autoimmune 30 forms of SAN dysfunction associated with disturbances of atrioventricular conduction.…”

A low voltage activated Ca2+ current found in a subset of human ventricular myocytes

“…As TTCCs remain in the sinoatrial and atrioventricular node and the conduction system, it has been proposed that the major function of TTCCs in adult hearts is to initiate cardiac rhythm and regulate cardiac conduction [ 2 ]. Recently, we showed that TTCCs play an important role in heart rate regulation by the sympathetic/β-adrenergic system [ 9 ]. I Ca-T expression in rat atrial myocytes decreases during postnatal development [ 10 , 11 ].…”