Expression of T‐ and L‐type calcium channel mRNA in murine sinoatrial node

Bohn, Georg; Moosmang, Sven; Conrad, Heinke; Ludwig, A.; Hofmann, Franz; Klugbauer, Norbert

doi:10.1016/s0014-5793(00)01979-7

Cited by 88 publications

(60 citation statements)

References 23 publications

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“…2B). To this respect, our data are consistent with previous results showing that both Ca v 1.3 and Ca v 1.2 expression can be detected in the whole SAN region by in situ hybridization (14). However, the possibility that a currently unknown gene coding for I Ca,L channels could also be involved in the generation of I Ca,L in SAN cannot be excluded (15).…”

Section: Discussionsupporting

confidence: 92%

Functional role of L-type Ca _v 1.3 Ca ²⁺ channels in cardiac pacemaker activity

Mangoni

Couette²,

Bourinet³

et al. 2003

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

426

487

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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.

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Section: Discussionsupporting

confidence: 92%

Functional role of L-type Ca _v 1.3 Ca ²⁺ channels in cardiac pacemaker activity

Mangoni

Couette²,

Bourinet³

et al. 2003

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

426

487

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“…Although mRNAs for all three Ca v 3 subtypes are expressed in brain, they vary in terms of their peripheral expression, and only Ca v 3.1 and Ca v 3.2 are expressed in the heart. Ca v 3.1 mRNA expression is 30-fold greater in SAN cells of the mouse than in atrial cells (10). Ca v 3.2 is also present, although only in moderate amounts (10).…”

Section: Voltage-dependent Camentioning

confidence: 90%

Pathophysiological Significance of T-type Ca2+ Channels: Properties and Functional Roles of T-type Ca2+ Channels in Cardiac Pacemaking

Ono

Iwamoto

2005

J Pharmacol Sci

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Abstract. Calcium channels are essential for excitation-contraction coupling and pacemaker activity in cardiac myocytes. While L-type Ca 2+ channels (LCC) have been extensively studied, functional roles of T-type channels (TCC) in native cardiac myocytes are still debatable. TCC are activated at more negative membrane potentials than LCC and therefore facilitate slow diastolic depolarization in sinoatrial node cells. Recent studies showed that selective inhibition of TCC produced a marked slowing of the pacemaker rhythm, indicating that contribution of TCC to cardiac automaticity was relatively larger than what had been speculated in previous studies. To re-evaluate TCC, we measured current density and kinetics of TCC in sinoatrial node cells of various mammalian species. Current density of TCC was larger in mice and guinea pigs than in rabbit and porcine sinoatrial node cells. Interestingly, few or no obvious TCC were recorded in porcine sinoatrial node cells. Furthermore, it was demonstrated that TCC could be enhanced by several vasoactive substances, thereby increasing spontaneous firing rate of sinoatrial node cells. TCC may, at least in part, account for different heart rates among various mammalian species. In addition, TCC might be involved in physiological and / or pathophysiological modulations of the heart rate.

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“…In fact, careful measurement of the nickel dose response in guinea pig atrium revealed a biphasic response, with 80% of the channels being blocked with an apparent IC 50 of 23 M, while 20% of the channels were inhibited with an IC 50 of 1,350 M. Rabbit and cat SAN cells appear to predominantly express Ca v 3.2 channels. In contrast, in situ hybridization of mouse heart suggests that Ca v 3.1 channels predominate, although both isoforms were readily detected and both were enriched in SAN relative to atrium (49). It should be noted that distinct in situ probes might differ in their ability to detect their cognate sequence, making such comparisons difficult.…”

Section: Heartmentioning

confidence: 93%

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Perez‐Reyes

2003

Physiological Reviews

1,501

1,446

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T-type Ca2+ channels were originally called low-voltage-activated (LVA) channels because they can be activated by small depolarizations of the plasma membrane. In many neurons Ca2+ influx through LVA channels triggers low-threshold spikes, which in turn triggers a burst of action potentials mediated by Na+ channels. Burst firing is thought to play an important role in the synchronized activity of the thalamus observed in absence epilepsy, but may also underlie a wider range of thalamocortical dysrhythmias. In addition to a pacemaker role, Ca2+ entry via T-type channels can directly regulate intracellular Ca2+ concentrations, which is an important second messenger for a variety of cellular processes. Molecular cloning revealed the existence of three T-type channel genes. The deduced amino acid sequence shows a similar four-repeat structure to that found in high-voltage-activated (HVA) Ca2+ channels, and Na+ channels, indicating that they are evolutionarily related. Hence, the α1-subunits of T-type channels are now designated Cav3. Although mRNAs for all three Cav3 subtypes are expressed in brain, they vary in terms of their peripheral expression, with Cav3.2 showing the widest expression. The electrophysiological activities of recombinant Cav3 channels are very similar to native T-type currents and can be differentiated from HVA channels by their activation at lower voltages, faster inactivation, slower deactivation, and smaller conductance of Ba2+. The Cav3 subtypes can be differentiated by their kinetics and sensitivity to block by Ni2+. The goal of this review is to provide a comprehensive description of T-type currents, their distribution, regulation, pharmacology, and cloning.

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Expression of T‐ and L‐type calcium channel mRNA in murine sinoatrial node

Cited by 88 publications

References 23 publications

Functional role of L-type Ca _v 1.3 Ca ²⁺ channels in cardiac pacemaker activity

Functional role of L-type Ca _v 1.3 Ca ²⁺ channels in cardiac pacemaker activity

Pathophysiological Significance of T-type Ca2+ Channels: Properties and Functional Roles of T-type Ca2+ Channels in Cardiac Pacemaking

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

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Expression of T‐ and L‐type calcium channel mRNA in murine sinoatrial node

Cited by 88 publications

References 23 publications

Functional role of L-type Ca v 1.3 Ca 2+ channels in cardiac pacemaker activity

Functional role of L-type Ca v 1.3 Ca 2+ channels in cardiac pacemaker activity

Pathophysiological Significance of T-type Ca2+ Channels: Properties and Functional Roles of T-type Ca2+ Channels in Cardiac Pacemaking

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

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Functional role of L-type Ca _v 1.3 Ca ²⁺ channels in cardiac pacemaker activity

Functional role of L-type Ca _v 1.3 Ca ²⁺ channels in cardiac pacemaker activity