Calcium Channels in the Heart: Disease States and Drugs
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Abstract:
Calcium ions are the major signaling ions in the cells. They regulate muscle contraction, neurotransmitter secretion, cell growth and migration, and the activity of several proteins including enzymes and ion channels and transporters. They participate in various signal transduction pathways, thereby regulating major physiological functions. Calcium ion entry into the cells is regulated by specific calcium channels and transporters. There are mainly six types of calcium channels, of which only two are prominent in the heart. In cardiac tissues, the two types of calcium channels are the L type and the T type. L-type channels are found in all cardiac cells and T-type are expressed in Purkinje cells, pacemaker and atrial cells. Both these types of channels contribute to atrioventricular conduction as well as pacemaker activity. Given the crucial role of calcium channels in the cardiac conduction system, mutations and dysfunctions of these channels are known to cause several diseases and disorders. Drugs targeting calcium channels hence are used in a wide variety of cardiac disorders including but not limited to hypertension, angina, and arrhythmias. This review summarizes the type of cardiac calcium channels, their function, and disorders caused by their mutations and dysfunctions. Finally, this review also focuses on the types of calcium channel blockers and their use in a variety of cardiac disorders.Keywords:
Calcium Signaling
Cardiac action potential
P-type calcium channel
L-type calcium channel
Stretch-activated ion channel
BK channel
SK channel
Calcium-activated potassium channel
Stretch-activated ion channel
Cardiac action potential
R-type calcium channel
Afterhyperpolarization
P-type calcium channel
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Contraction of smooth muscle is initiated, and to a lesser extent maintained, by a rise in the concentration of free calcium in the cell cytoplasm ([Ca 2+ ] i ). This activator calcium can originate from two intimately linked sources – the extracellular space and intracellular stores, most notably the sarcoplasmic reticulum. Smooth muscle contraction activated by excitatory neurotransmitters or hormones usually involves a combination of calcium release and calcium entry. The latter occurs through a variety of calcium permeable ion channels in the sarcolemma membrane. The best‐characterized calcium entry pathway utilizes voltage‐operated calcium channels (VOCCs). However, also present are several types of calcium‐permeable channels which are non‐voltage‐gated, including the so‐called receptor‐operated calcium channels (ROCCs), activated by agonists acting on a range of G‐protein‐coupled receptors, and store‐operated calcium channels (SOCCs), activated by depletion of the calcium stores within the sarcoplasmic reticulum. In this article we will review the electrophysiological, functional and pharmacological properties of ROCCs and SOCCs in smooth muscle and highlight emerging evidence that suggests that the two channel types may be closely related, being formed from proteins of the Transient Receptor Potential Channel (TRPC) family. British Journal of Pharmacology (2002) 135 , 1–13; doi: 10.1038/sj.bjp.0704468
Stretch-activated ion channel
Sarcolemma
P-type calcium channel
R-type calcium channel
Calcium Signaling
Calcium in biology
Calcium ATPase
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Tottering mice inherit a recessive mutation of the calcium channel α1A subunit that causes ataxia, polyspike discharges, and intermittent dystonic episodes. The calcium channel α1Asubunit gene encodes the pore-forming protein of P/Q-type voltage-dependent calcium channels and is predominantly expressed in cerebellar granule and Purkinje neurons with moderate expression in hippocampus and inferior colliculus. Because calcium misregulation likely underlies the tottering mouse phenotype, calcium channel blockers were tested for their ability to block the motor episodes. Pharmacologic agents that specifically block l-type voltage-dependent calcium channels, but not P/Q-type calcium channels, prevented the inducible dystonia of tottering mutant mice. Specifically, the dihydropyridines nimodipine, nifedipine, and nitrendipine, the benzothiazepine diltiazem, and the phenylalkylamine verapamil all prevented restraint-induced tottering mouse motor episodes. Conversely, the l-type calcium channel agonist Bay K8644 induced stereotypic tottering mouse dystonic at concentrations significantly below those required to induce seizures in control mice. In situ hybridization demonstrated thatl-type calcium channel α1C subunit mRNA expression was up-regulated in the Purkinje cells of tottering mice. Radioligand binding with [3H]nitrendipine also revealed a significant increase in the density of l-type calcium channels in tottering mouse cerebellum. These data suggest that although a P/Q-type calcium channel mutation is the primary defect in tottering mice, l-type calcium channels may contribute to the generation of the intermittent dystonia observed in these mice. The susceptibility of l-type calcium channels to voltage-dependent facilitation may promote this abnormal motor phenotype.
Nitrendipine
P-type calcium channel
L-type calcium channel
R-type calcium channel
Bay K8644
N-type calcium channel
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T-type calcium channels are low-threshold voltage-gated calcium channel and characterized by unique electrophysiological properties such as fast inactivation and slow deactivation kinetics. All subtypes of T-type calcium channel (Cav3.1, 3.2 and 3.3) are widely expressed in the central nerve system, and they have an important role in homeostasis of sleep, pain response, and development of epilepsy. Recently, several reports suggest that T-type calcium channels may mediate neuronal plasticity in the mouse brain. We succeeded to develop T-type calcium channel enhancer ethyl 8'-methyl-2',4-dioxo-2-(piperidin-1-yl)-2'H-spiro[cyclopentane-1,3'-imidazo[1,2-a]pyridine]-2-ene-3-carboxylate (SAK3) which enhances Cav3.1 and 3.3 currents in each-channel expressed neuro2A cells. SAK3 can promote acetylcholine (ACh) release in the mouse hippocampus via enhancing T-type calcium channel. In this review, we have introduced the role of T-type calcium channel, especially Cav3.1 channel in the mouse hippocampus based on our previous data using SAK3 and Cav3.1 knockout mice.
P-type calcium channel
N-type calcium channel
R-type calcium channel
L-type calcium channel
Mibefradil
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Voltage-gated calcium channels are important for the depolarization-evoked contraction of vascular smooth muscle cells (SMCs), with L-type channels being the classical channel involved in this mechanism. However, it has been demonstrated that the CaV2.1 subunit, which encodes a neuronal isoform of the voltage-gated calcium channels (P/Q-type), is also expressed and contributes functionally to contraction of renal blood vessels in both mice and humans. Furthermore, preglomerular vascular SMCs and aortic SMCs coexpress L-, P-, and Q-type calcium channels within the same cell. Calcium channel blockers are widely used as pharmacological treatments. However, calcium channel antagonists vary in their selectivity for the various calcium channel subtypes, and the functional contribution from P/Q-type channels as compared with L-type should be considered. Confirming the presence of P/Q-type voltage-gated calcium channels in other types of vascular SMCs could be important when investigating phenomena such as hypertension, migraine, and other diseases known to involve SMCs and voltage-gated calcium channels. The purpose of this review was to give a short overview of the possible roles of P/Q-type calcium channels within the vascular system with special focus on the renal vasculature.
N-type calcium channel
L-type calcium channel
R-type calcium channel
P-type calcium channel
Cardiac action potential
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P-type calcium channel
R-type calcium channel
N-type calcium channel
L-type calcium channel
Cardiac muscle
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Nitrendipine
Disinhibition
L-type calcium channel
P-type calcium channel
N-type calcium channel
Calcium-activated potassium channel
SK channel
Calcium channel blocker
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P-type calcium channel
L-type calcium channel
R-type calcium channel
N-type calcium channel
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Cardiac action potential
L-type calcium channel
N-type calcium channel
R-type calcium channel
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Cognitive and functional decline with age is correlated with deregulation of intracellular calcium, which can lead to neuronal death in the brain. Previous studies have found protective effects of various calcium channel blockers in pathological conditions. However, little has been done to explore possible protective effects of blockers for T-type calcium channels, which forms a family of FDA approved anti-epileptic drugs. In this study, we found that neurons showed an increase in viability after treatment with either L-type or T-type calcium channel antagonists. The family of low-voltage activated, or T-type calcium channels, comprise of three members (Cav3.1, Cav3.2, and Cav3.3) based on their respective main pore-forming alpha subunits: alpha1G, alpha1H, and alpha1I. Among these three subunits, alpha1H is highly expressed in hippocampus and certain cortical regions. However, T-type calcium channel blockers can protect neurons derived from alpha1H-/- mice, suggesting that neuroprotection demonstrated by these drugs is not through the alpha1H subunit. In addition, blockers for T-type calcium channels were not able to confer any protection to neurons in long-term cultures, while blockers of L-type calcium channels could protect neurons. These data indicate a new function of blockers for T-type calcium channels, and also suggest different mechanisms to regulate neuronal survival by calcium signaling pathways. Thus, our findings have important implications in the development of new treatment for age-related neurodegenerative disorders.
L-type calcium channel
P-type calcium channel
R-type calcium channel
Calcium in biology
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