CaV1.3 L-type Ca(2+) channel contributes to the heartbeat by generating a dihydropyridine-sensitive persistent Na(+) current (original) (raw)
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Functional role of L-type Cav1.3 Ca2+ channels in cardiac pacemaker activity
Proceedings of the National Academy of Sciences, 2003
The spontaneous activity of pacemaker cells in the sino-atrial node (SAN) controls the heart rhythm and rate under physiological conditions. Pacemaker activity in SAN cells is due to the presence of the diastolic depolarization, a slow depolarization phase that drives the membrane voltage from the end of an action potential to the threshold of a new action potential. SAN cells express a wide array of ionic channels, but we have limited knowledge about their functional role in pacemaker activity and we still do not know which channels play a prominent role in the generation of the diastolic depolarization. It is thus important to provide genetic evidence linking the activity of genes coding for ionic channels to specific alterations of pacemaker activity of SAN cells. Here, we show that target inactivation of the gene coding for ␣1D (Cav1.3) Ca 2؉ channels in the mouse not only significantly slows pacemaker activity but also promotes spontaneous arrhythmia in SAN pacemaker cells. These alterations of pacemaker activity are linked to abolition of the major component of the L-type current (I Ca,L) activating at negative voltages. Pharmacological analysis of I Ca,L demonstrates that Cav1.3 gene inactivation specifically abolishes I Ca,L in the voltage range corresponding to the diastolic depolarization. Taken together, our data demonstrate that Ca v1.3 channels play a major role in the generation of cardiac pacemaker activity by contributing to diastolic depolarization in SAN pacemaker cells.
American journal of physiology. Heart and circulatory physiology, 2016
Coupling of an intracellular Ca(2+) clock to surface membrane ion channels, i.e., a "membrane clock, " via coupling of electrochemical Na(+) and Ca(2+) gradients (ENa and ECa, respectively) has been theorized to regulate sinoatrial nodal cell (SANC) normal automaticity. To test this hypothesis, we measured responses of [Na(+)]i, [Ca(2+)]i, membrane potential, action potential cycle length (APCL), and rhythm in rabbit SANCs to Na(+)/K(+) pump inhibition by the digitalis glycoside, digoxigenin (DG, 10-20 μmol/l). Initial small but significant increases in [Na(+)]i and [Ca(2+)]i and reductions in ENa and ECa in response to DG led to a small reduction in maximum diastolic potential (MDP), significantly enhanced local diastolic Ca(2+) releases (LCRs), and reduced the average APCL. As [Na(+)]i and [Ca(2+)]i continued to increase at longer times following DG exposure, further significant reductions in MDP, ENa, and ECa occurred; LCRs became significantly reduced, and APCL became ...
Voltage-dependent calcium channels and cardiac pacemaker activity: From ionic currents to genes
Progress in Biophysics and Molecular Biology, 2006
The spontaneous activity of pacemaker cells in the sino-atrial node controls the heart rhythm and rate under physiological conditions. Compared to working myocardial cells, pacemaker cells express a specific array of ionic channels. The functional importance of different ionic channels in the generation and regulation of cardiac automaticity is currently subject of an extensive research effort and has long been controversial. Among families of ionic channels, Ca 2+ channels have been proposed to substantially contribute to pacemaking. Indeed, Ca 2+ channels are robustly expressed in pacemaker cells, and influence the cell beating rate. Furthermore, they are regulated by the activity of the autonomic nervous system in both a positive and negative way. In this manuscript, we will first discuss how the concept of the involvement of Ca 2+ channels in cardiac pacemaking has been proposed and then subsequently developed by the recent advent in the domain of cardiac physiology of gene-targeting techniques. Secondly, we will indicate how the specific profile of Ca 2+ channels expression in pacemaker tissue can help design drugs which selectively regulate the heart rhythm in the absence of concomitant negative inotropism. Finally, we will indicate how the new possibility to assign a specific gene activity to a given ionic channel involved in ARTICLE IN PRESS www.elsevier.com/locate/pbiomolbio 0079-6107/$ -see front matter r (M.E. Mangoni).
The Journal of Physiology, 2012
• In the sinoatrial node (SAN), Ca v 1 voltage-gated Ca 2+ channels mediate L-type currents that are essential for normal cardiac pacemaking. • Both Ca v 1.2 and Ca v 1.3 Ca 2+ channels are expressed in the SAN but how their distinct properties affect cardiac pacemaking is unknown. • Here, we show that unlike Ca v 1.2, Ca v 1.3 undergoes voltage-dependent facilitation and colocalizes with ryanodine receptors in sarcomeric structures. • By mathematical modelling, these properties of Ca v 1.3 can improve recovery of pacemaking after pauses and stabilize SAN pacemaking during excessively slow heart rates. • We conclude that voltage-dependent facilitation and colocalization with ryanodine receptors distinguish Ca v 1.3 from Ca v 1.2 channels in the SAN and contribute to the major impact of Ca v 1.3 on pacemaking.
Cardiovascular and Hematological Disorders - Drug Targets, 2006
The generation of cardiac pacemaker activity is a complex phenomenon which requires the coordinated activity of different membrane ionic channels, as well as intracellular signalling factors including Ca 2+ and second messengers. The precise mechanism initiating automaticity in primary pacemaker cells is still matter of debate and certain aspects of how channels cooperate in the regulation of pacemaking by the autonomic nervous system have not been entirely elucidated. Research in the physiopathology of cardiac automaticity has also gained a considerable interest in the domain of cardiovascular pharmacology, since accumulating clinical and epidemiological evidence indicate a link between an increase in heart rate and the risk of cardiac mortality and morbidity. Lowering the heart rate by specific bradycardic agents in patients with heart disease constitutes a promising way to increase cardioprotection and improve survival. Thus, the elucidation of the mechanisms underlying the generation of pacemaker activity is necessary for the development of new therapeutic molecules for controlling the heart rate. Recent work on genetically modified mouse models provided new and intriguing evidence linking the activity of ionic channels genes to the generation and regulation of pacemaking. Importantly, results obtained on genetically engineered mouse strains have demonstrated that some channels are specifically involved in the generation of cardiac automaticity and conduction, but have no functional impact on the contractile activity of the heart. In this article, we will outline the current knowledge on the role of ionic channels in cardiac pacemaker activity and suggest new potential pharmacological targets for controlling the heart rate without concomitant negative inotropism.
Cell Biochemistry and Function, 2012
Voltage-gated Ca 2+ channels regulate cardiac automaticity, rhythmicity and excitation-contraction coupling. Whereas L-type (Ca v 1Á2, Ca v 1Á3) and T-type (Ca v 3Á1, Ca v 3Á2) channels are widely accepted for their functional relevance in the heart, the role of Ca v 2Á3 Ca 2+ channels expressing R-type currents remains to be elucidated. We have investigated heart rate dynamics in control and Ca v 2Á3-deficient mice using implantable electrocardiogram radiotelemetry and pharmacological injection experiments. Autonomic block revealed that the intrinsic heart rate does not differ between both genotypes. Systemic administration of isoproterenol resulted in a significant reduction in interbeat interval in both genotypes. It remained unaffected after administering propranolol in Ca v 2Á3(À|À) mice. Heart rate from isolated hearts as well as atrioventricular conduction for both genotypes differed significantly. Additionally, we identified and analysed the developmental expression of two splice variants, i.e. Ca v 2Á3c and Ca v 2Á3e. Using patch clamp technology, R-type currents could be detected in isolated prenatal cardiomyocytes and be related to R-type Ca 2+ channels. Our results indicate that on the systemic level, the pharmacologically inducible heart rate range and heart rate reserve are impaired in Ca v 2Á3 (À|À) mice. In addition, experiments on Langendorff perfused hearts elucidate differences in basic properties between both genotypes. Thus, Ca v 2Á3 does not only contribute to the cardiac autonomous nervous system but also to intrinsic rhythm propagation.
Requirement of neuronal- and cardiac-type sodium channels for murine sinoatrial node pacemaking
The Journal of Physiology, 2004
The majority of Na + channels in the heart are composed of the tetrodotoxin (TTX)-resistant (K D , 2-6 µM) Na v 1.5 isoform; however, recently it has been shown that TTX-sensitive (K D , 1-10 nM) neuronal Na + channel isoforms (Na v 1.1, Na v 1.3 and Na v 1.6) are also present and functionally important in the myocytes of the ventricles and the sinoatrial (SA) node. In the present study, in mouse SA node pacemaker cells, we investigated Na + currents under physiological conditions and the expression of cardiac and neuronal Na + channel isoforms. We identified two distinct Na + current components, TTX resistant and TTX sensitive. At 37 • C, TTX-resistant i Na and TTX-sensitive i Na started to activate at ∼ −70 and ∼ −60 mV, and peaked at −30 and −10 mV, with a current density of 22 ± 3 and 18 ± 1 pA pF −1 , respectively. TTX-sensitive i Na inactivated at more positive potentials as compared to TTX-resistant i Na . Using action potential clamp, TTX-sensitive i Na was observed to activate late during the pacemaker potential. Using immunocytochemistry and confocal microscopy, different distributions of the TTX-resistant cardiac isoform, Na v 1.5, and the TTX-sensitive neuronal isoform, Na v 1.1, were observed: Na v 1.5 was absent from the centre of the SA node, but present in the periphery of the SA node, whereas Na v 1.1 was present throughout the SA node. Nanomolar concentrations (10 or 100 nM) of TTX, which block TTX-sensitive i Na , slowed pacemaking in both intact SA node preparations and isolated SA node cells without a significant effect on SA node conduction. In contrast, micromolar concentrations (1-30 µM) of TTX, which block TTX-resistant i Na as well as TTX-sensitive i Na , slowed both pacemaking and SA node conduction. It is concluded that two Na + channel isoforms are important for the functioning of the SA node: neuronal (putative Na v 1.1) and cardiac Na v 1.5 isoforms are involved in pacemaking, although the cardiac Na v 1.5 isoform alone is involved in the propagation of the action potential from the SA node to the surrounding atrial muscle.
Biophysical Journal, 2012
OBJECTIVE The L-type Ca 2ϩ current (I Ca,L) and the Na ϩ /Ca 2ϩ exchange current (I NCX) are major inward currents that shape the cardiac action potential (AP). Previously, the profile of these currents during the AP was determined from voltage-clamp experiments that used Ca 2ϩ buffer. In this study, we aimed to obtain direct experimental measurement of these currents during cardiac AP with Ca 2ϩ cycling. METHOD A newly developed AP-clamp sequential dissection method was used to record ionic currents in guinea pig ventricular myocytes under a triad of conditions: using the cell's own AP as the voltage command, using internal and external solutions that mimic the cell's ionic composition, and, importantly, not using any exogenous Ca 2ϩ buffer. RESULTS The nifedipine-sensitive current (I NIFE), which is composed of I Ca,L and I NCX , revealed hitherto unreported features during the AP with Ca 2ϩ cycling in the cell. We identified 2 peaks in the current profile followed by a long residual current extending beyond the AP, coinciding with a residual depolarization. The second peak and the residual current become apparent only when Ca 2ϩ is not buffered. Pharmacological dissection of I NIFE by using SEA0400 shows that I Ca,L is dominant during phases 1 and 2 whereas I NCX contributes significantly to the inward current during phases 3 and 4 of the AP. CONCLUSION These data provide the first direct experimental visualization of I Ca,L and I NCX during cardiac the AP and Ca 2ϩ cycle. The residual current reported here can serve as a potential substrate for afterdepolarizations when increased under pathologic conditions. KEYWORDS Cardiac Ventricular; Myocyte; Action potential; L-type Ca 2ϩ channel; Na ϩ /Ca 2ϩ exchanger; Arrhythmia ABBREVIATIONS AP ϭ Action potential; CDI ϭ Ca 2ϩ-dependent inactivation; I Ca,L ϭ L-type Ca 2ϩ current; I NCX ϭ Na ϩ /Ca 2ϩ exchange current; I NIFE ϭ nifedipine-sensitive current; ISEA ϭ SEAsensitive current