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

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Calcium channels – basic aspects of their structure_ function _amp; gene Powered By Docstoc
					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 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
  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/Q-   R-type
                                           type
Voltage      LVA      HVA        HVA       HVA    IVA
dependen
ce
Threshold -70         -20        -30_-10   -60    -40
activation
(mV)
Inactivati -100_-60   -120_-30   -60_-10
on
range(mV
)
Rate of      20_50    50_80      >500
inactivati
on(msec)
         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
  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:
•   a1 , a2 , g , & b.
•   It plays a role in some forms of neurotransmitter
    release.
• 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

         HVA
         a1A            CACNA1A        19p13.1-2      Brain,neuronal          P / Q –type
                                                      cells,heart
         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

         IVA
         a1E            CACNA1E        1q25-q31       Brain,neuronal cells    R-type

         LVA
         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
    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

 VA           HVA          HVA         HVA          IVA        LVA

location      heart        Neuronal    Neuronal     Neuronal   Heart


function      Contractio   Release     Release      Release    Pacemaker
              n

Anesthetic
interaction
Volatile      Sensitive    Sensitive   Controvers   Unknown    Sensitive
                                       ial
intravenous   Sensitive    Sensitive   Controvers   Unknown    Controvers
                                       ial                     ial
                 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 ).

				
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posted:7/23/2013
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