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Calcium channels – basic aspects of their structure, function & gene encoding; anesthetic action on the channels – a review Tariq Alzahrani Demonstrator College of Medicine King Saud University Introduction • Intracellular ca+2 conce. 100 nM. • Extracellular ca+2 conce. 1 mM. • Intracellular to extracellular of free ca+2 conce. is 1/10,000. • This conce. gradient is maintained by 3 main mechanisms : • 1. Extrusion ( ca+2 – ATPase ) • 2. Sequestration ( releasable & non releasable ) • 3. Binding • When the cells are stimulated by some receptor agonists, ca+2 conce. increases from resting level to approximately 1M. • Intracellular ca+2 conc. may be elevated by opening membrane ca+2 channels or releasing ca+2 from intracellular (releasable) storage sites. • There are 2 classes of ca+2 channels: • 1. Voltage- Sensitive (VDCCs) • 2. Receptor- Operated (Ligand- Gated ion channels) VDCCs Classification • The possible existence of VDCCs was first reported by Hagiwara in 1975 using egg cell membrane of a starfish. • They were initially divided into 2 classes HVA & LVA ca+2 channels. • HVA ca+2 channels are further divided into L,N,P/Q & R-types channels, while LVA ca+2 channels consists of only T-type channels. • R-type is occasionally classified as ( IVA ) channels. T-type N-type L-type P/Qtype R-type LVA HVA HVA HVA IVA Threshold -70 activation (mV) -20 -30_-10 -60 -40 Inactivati -100_-60 on range(mV ) -120_-30 -60_-10 Rate of inactivati on(msec) 50_80 >500 Voltage dependen ce 20_50 Structure & Function • L-type ca+2 channel : • It is high conce. in skeletal muscle. • It is composed of 5 different polypeptide subunits, having different molecular masses: • 1.1(175KD) , which forms the ion channel & contains ca+2 antagonist binding sites. • 2.2(143KD), which is associated with 1 & does not contain any high-affinity binding site. • 3.(54KD), 4.(30KD), 5.(27KD). • L-type ca+2 channels are linked to ryanodine receptor of sarcoplasmic reticulum. • Abnormal ryanodine receptor causes malignant hyperthermia which is a hypermetabolic crisis triggered by suxamethonium & volatile anesthetics. • However, as yet, there has been no report on the effects of anesthetics on abnormal L-type ca+2 channel activity in malignant hyperthermia. • The functions of the L-type ca+2 channel are related to the generation of action potentials & to signal transduction events at the cell membrane. • Except the platelets, L-type VDCCs are expressed ubiquitously in neuronal, endocrine, cardiac, smooth, & skeletal muscle, as well as in fibroblasts & kidney cells. • Recent report suggest a role for L-type VDCCs in the process of neurotransmitter secretion of the central nervous system. • N-type ca channel : • • • • It is purified from the rat brain. It is composed of 4 subunits: 1 , 2 , , & . It plays a role in some forms of neurotransmitter release. • P/Q-type ca channel : • It is composed of 1, 2, & subunits. • Immunohistological studies have shown that the P/Q-type channel is widely expressed in the mammalian central nervous system & that the channel appears to serve both as a generator of intrinsic activity & as a modulator of neuronal integration & transmitter release. • T-type ca channel : • Because T-type VDCCs are activated at negative membrane potentials close to the resting potential, the T-type channel is thought to be responsible for neuronal oscillatory activity, which is proposed to be involved in process such as sleep / wakefulness regulation & motor coordination. • In addition ,T-type ca+2 channels are involved in pacemaker activity. Channel gene Isoform Gene name Chromosomal localization Tissue distribution Biophysical properties HVA 1A CACNA1A 19p13.1-2 P / Q –type 1B CACNA1B 9q34 Brain,neuronal cells,heart Brain,neuronal cells 1C 1D CACNA1C CACNA1D 12p13.3 3p14.3 Ubiquitous Brain,neuronal,cells ,endocrine cells L-type L-type 1F 1S CACNA1F CACNA1S Xp11.23 1q31-q32 Skeletal muscle L-type L-type IVA 1E CACNA1E 1q25-q31 Brain,neuronal cells R-type LVA 1G 1H CACNA1G CACNA1H 17q22 16p13.3 Brain Kidney,liver,heart T-type T-type 1I CACNA1I 22q13 Brain T-type N-type The main subunit 1 can function as ca+2 channel. Other subunits (2 / & ) contribute to the regulation of a ca+2 channel function by changing drug affinity & / or voltage dependence. Receptor – Operated Channels ( Ligand – Gated Ion Channels) • It is found on the plasma membrane & is composed of 4 or 5 subunits in various combinations depending on the particular receptor. Effects of anesthetics on channel activity Volatile anesthetics • Ikemoto first demonstrated in 1985 that halothane decreased inward ca+2 slow currents in ventricular myocytes in rats, & then Terrar reported the inhibitory effect of halothane & isoflurane on ca+2 channels of cardiac myocytes from the guinea pig ventricle. • In general , volatile anesthetics at clinically relevant conces. inhibit inward currents through VDCCs in a dose-dependent manner without an apparent change in the time course of activation or inactivation. • Volatile anesthetics do not alter the voltage dependence of the currents. • Based on the percent anesthetic conces. in the gas phase, the order of inhibitory potencies for the currents is halothane > isoflurane / enflurane > sevoflurane. • Single channel analysis has shown that halothane decreased the likelihood of channel opening & enhanced the rate at which the channel closed & became inactivated. • Recent studies have revealed that the receptors for inhibitory neurotransmitters such as GABA & glycine are sensitive to volatile anesthetics at clinically relevant concentration. Intravenous anesthetics • Ikemoto also demonstrated the inhibitory effect of thiamylal on ca+2 inward current in rat ventricular cell. • Propofol also has significant inhibitory effects on T & L- type components of the ca+2 current in cultured dorsal root ganglion neurons from chick embryos, this inhibition might play a role in cardiovascular side effect observed clinically. • Ketamine in vitro showed inhibitory effects on activation & inactivation of ca+2 currents of ventricular myocytes in guinea pig, leading to the direct myocardiac depression. However , ketamine can support vascular tone & cardiac function presumably secondary to ketamine-induced catecholamine release. • Also ketamine have their own binding site on the N-methyl-D-aspartat ( NMDA ) receotpr. • The I.V anesthetics thiopental, ketamine & propofol all inhibited inward ca+2 currents through L- type VDCCs of porcine tracheal smooth muscle cells, demonstrating a cellular effect of these anesthetics that can account for their airway smooth muscle relaxant effects. • Thiopental, ketamine & propofol showed similar effects on activation & inactivation of ca+2 currents; however, the concentration required to produce these effects appear to be substantially higher than the free conces. observed clinically in serum. • Benzodiazepines have their own binding site on the GABAa receptor & the clinical effect of these drugs ( e.g, sedation, amnesia & anticonvulsion ) may be accounted for by these interaction. • Other investigators have also found that benzodiazepines had inhibitory effects on L- type VDCCs in canine myocardial cells, in canine tracheal smooth muscle cells & porcine intestinal mucosa cells. Local anesthetics • Lidocaine at clinically relevant conces. has been shown to inhibit inward ca+2 currents in Helix ganglionic neurons & in frog dorsal root ganglionic cells. • Lidocaine, tetracaine & bupivacaine also inhibit the VDCC activity of cardiac myocytes in the chick, guinea pig & hamster, respectively. • The inhibition is voltage-dependent & the peak amplitude of the ca+2 current cannot be restored to the control level by washout. • Note : the inhibition by local anesthetics of VDCCs in cardiac myocytes might contribute to local anesthetic-induced cardiodepression. summary L N P/Q R T HVA HVA HVA IVA LVA location heart Neuronal Neuronal Neuronal Heart function Contractio n Release Release Release Pacemaker Anesthetic interaction Volatile Sensitive Sensitive Unknown Sensitive intravenous Sensitive Sensitive Controvers ial Controvers ial Unknown Controvers ial VA Conclusions • Intracellular free ca+2 is important for regulation of cell function. • Increase in conce. of intracellular free ca+2 can be obtained by rapid but transient ca+2 release from intracellular ca+2 stores & by slow ca+2 influx from the extracellular space. • VDCCS serve as one of the important mechanisms for ca+2 influx into the cells, enabling the regulation of intracellular free ca+2 concentration. • The ca+2 channel can be divided into subtypes according to their electrophysiological characteristics & each subtype is encoded by its own gene. • The effects of various kinds of anesthetics in a variety of cell types have been demonstrated & a number of clinical effects of anesthetics can be explained by their effects on ca+2 channels. • Ligand-Gated ion channel is very important from the anesthetic viewpoint in that the nicotinic acetylcholine receptor is the target for neuromascular relaxants, the NMDA receptor is the target for ketamine & the GABAa receptor is a major target for a range of inhalation & intravenous general anesthetics agents ( excluding ketamine ).