Calcium channels – basic aspects of their structure_ function _amp; gene

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					Calcium channels – basic aspects
  of their structure, function &
gene encoding; anesthetic action
   on the channels – a review

           Tariq Alzahrani
          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
  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 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
  pacemaker activity.
                            Channel gene
         Isoform        Gene name      Chromosomal    Tissue distribution     Biophysical
                                       localization                           properties

         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
                                                      endocrine cells
         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
       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
• 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 &
  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
• 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
• 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.
                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
                                       ial                     ial
• 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 ).

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