Calcium channels – basic aspects
of their structure, function &
gene encoding; anesthetic action
on the channels – a review
College of Medicine
King Saud University
• Intracellular ca+2 conce. 100 nM.
• Extracellular ca+2 conce. 1 mM.
• Intracellular to extracellular of free ca+2 conce. is
• This conce. gradient is maintained by 3 main
• 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 1mM.
• 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
• 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 )
T-type N-type L-type P/Q- R-type
Voltage LVA HVA HVA HVA IVA
Threshold -70 -20 -30_-10 -60 -40
Inactivati -100_-60 -120_-30 -60_-10
Rate of 20_50 50_80 >500
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.a1(175KD) , which forms the ion channel &
contains ca+2 antagonist binding sites.
• 2.a2(143KD), which is associated with a1 & does
not contain any high-affinity binding site.
• 3.b(54KD), 4.g(30KD), 5.d(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
• 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:
• a1 , a2 , g , & b.
• It plays a role in some forms of neurotransmitter
• P/Q-type ca channel :
• It is composed of a1, a2, d & b 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
Isoform Gene name Chromosomal Tissue distribution Biophysical
a1A CACNA1A 19p13.1-2 Brain,neuronal P / Q –type
a1B CACNA1B 9q34 Brain,neuronal cells N-type
a1C CACNA1C 12p13.3 Ubiquitous L-type
a1D CACNA1D 3p14.3 Brain,neuronal,cells, L-type
a1F CACNA1F Xp11.23 L-type
a1S CACNA1S 1q31-q32 Skeletal muscle L-type
a1E CACNA1E 1q25-q31 Brain,neuronal cells R-type
a1G CACNA1G 17q22 Brain T-type
a1H CACNA1H 16p13.3 Kidney,liver,heart T-type
a1I CACNA1I 22q13 Brain T-type
The main subunit a1 can function as ca+2 channel. Other subunits (a2 / d & b) contribute to
the regulation of a ca+2 channel function by changing drug affinity & / or voltage
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
• 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
• 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
• 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 &
• Recent studies have revealed that the receptors for
inhibitory neurotransmitters such as GABA &
glycine are sensitive to volatile anesthetics at
clinically relevant concentration.
• Ikemoto also demonstrated the inhibitory effect of
thiamylal on ca+2 inward current in rat ventricular
• 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
• 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
• 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
• Lidocaine at clinically relevant conces. has been
shown to inhibit inward ca+2 currents in Helix
ganglionic neurons & in frog dorsal root
• 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.
L N P/Q R T
VA HVA HVA HVA IVA LVA
location heart Neuronal Neuronal Neuronal Heart
function Contractio Release Release Release Pacemaker
Volatile Sensitive Sensitive Controvers Unknown Sensitive
intravenous Sensitive Sensitive Controvers Unknown Controvers
• 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
• 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