Docstoc

Signal Transduction I

Document Sample
Signal Transduction I Powered By Docstoc
					 I: Signal Transduction

Regulation of cell permeability by
  ligand-gated channels: the
  nicotinic receptor and other
      ionotropic receptors
      Ionotropic vs metabotropic receptors

• Opening a channel directly, as is seen in the
  nicotinic ACh receptor, provides for very rapid
  transduction of chemical detection into an
  electrical signal – this is an example of an
  ionotropic receptor.
• As we will see, the muscarinic ACh receptor
  works in a completely different way…the
  different subtypes of muscarinic receptors are
  all metabotropic receptors – in which
  messenger-receptor binding works by initiating
  a 2nd message within the target cell.
What makes a given synapse
excitatory or inhibitory for the
postsynaptic cell?
 It depends on what happens after
transmitter binds receptor – not on
some intrinsic property of the
transmitter chemical itself .
Inhibitory Postsynaptic Potentials
(IPSPs)
All inhibitory mechanisms oppose
depolarization
Simplest mechanism: increased K+
permeability – which would lead to
hyperpolarization
Less simple: increased Cl- permeability
– sometimes called silent inhibition –
tends to stabilize membrane potential at
the rest value.
Skeletal Muscle Synapse: Nicotinic ACh receptors are
    the classic example of ligand-gated channels
    Points from preceding slide:
• Accumulation of ACh into the vesicles is driven by a H+
  pump.
• ACh synthesis occurs in the cytoplasm of the terminal.
• The channel that is opened by ACh is called “ligand
  gated”. Ligand-gated channels are opened or closed by
  lock-and-key binding with a chemical.
• The synaptic potential (end plate potential) is above
  threshold for an action potential.
• The action potential in muscle cells is similar to that in
  nerve cell axons: Na+ and K+ voltage-gated channels.
• The quick recovery from the ACh binding is the result of
  acetylcholinesterase, which terminates the
  neurotransmitter effect.
 Neuromuscular synaptic transmission: effect of
  ACh on nicotinic receptors of skeletal muscle
• 1. A single action potential releases so many vesicles
  that the depolarization of the muscle cell membrane
  reaches the threshold for an action potential –
  transmission is 1:1 – this is a unique synapse!
• The nicotinic acetylcholine receptor protein is a
  ligand-gated cation channel: it is a channel that
  allows passage of Na+ and K+ when ACh binds.
• Because the muscle resting potential is near the K+
  equilibrium potential, Na+ is the dominant ion that
  flows through the channel, exerting a depolarizing
  effect on the muscle cell membrane.
• Patch-clamping reveals that each channel remains
  open for 2-3 msec., allowing 15,000 – 30,000 Na+ to
  flow through.
The nicotonic ACh receptor is a pentameric channel
Toxins that target the ACh receptor have been
               tools for research

• The receptor gets its name from the fact that
  nicotine mimics the effect of ACh.
• a-bungarotoxin is produced by the snake called
  the banded Krait. Scientists in Taiwan showed
  that paralysis was the result of binding to the
  ACh receptor.
• Curare is a mixture of plant toxins (purified:
  tubocarine) used by S.A. Indians for arrowhead
  poison and in surgery to block muscle reflexes.
  It blocks the receptor and prevents ACh binding.
   More examples of ionotropic receptors
• The fast synaptic response seen upon
  activation of nicotinic ACh receptors is similar to
  the synaptic depolarization initiated by the 2
  glutamate ionotropic receptors: both Na+ and
  K+ can move through the channels.
• GABA (gamma amino butyric acid) and glycine
  receptors are Cl- channels. Their inhibitory
  effect is to either hyperpolarize the postsynaptic
  cell by increasing the Cl- permeability (if it is not
  at equilibrium) and/or to “clamp” the membrane
  potential at the resting state by making Cl-
  more dominant in determining the resting
  potential.
The GABAA receptor
and its binding sites
for drugs and
modulators

Benzodiazepines are
antidepressants;
barbiturates are
depressants; steroids
exert an
antidepressant effect;
pentobarbitol is a
‘local anesthetic’.
GABAA receptor: another ligand-gated channel
• The GABAA receptor has a hyperpolarizing
  effect on its target cell which is called an
  inhibitory postsynaptic potential = IPSP
• The effect of benzodiazapene is to increase the
  Cl- movement through the open channels; this
  inhibition has a calming effect, as its action is
  particularly important in brain regions associated
  with emotional behavior.
• Huntington’s chorea is a degenerative disease in
  which GABA-ergic (GABA-releasing) neurons
  are lost and the result is uncontrolled
  movements. The GABA-releasing neurons are
  thought to die off due to an inherited excessive
  activity by glutamate-releasing cells, one
  example of excitotoxicity.
      Metabotropic receptors
• What is a 2nd messenger? Any substance
  that is released inside the cell or
  synthesized there in response to
  messenger-receptor binding at the cell
  surface, and that effects the target cell’s
  response to the 1st message.
        Why 2nd messages?
• 2nd messages can do more than just affect
  the electrical responsiveness of the target
  cells
• 2nd messages reach effectors within the
  cell and can also affect gene expression
• 2nd messages amplify the 1st message-
  generally this is the outcome of a
  multistage signal cascade.
Second messenger amplification increases
 the ligand’s effect, but this takes time…
     Opening ion
   channels is only
  one of the effects
  that such second
  messengers can
 have. A few of the
other pathways are
    included here.
Although not all are
 present in any one
example, more than
one change is often
activated by binding
     of the ligand.
     The 3 major 2nd messenger
             systems
• Cyclic nucleotides (cAMP, cGMP)
• Inositol trisphosphate (IP3)
• Ca++
  – Interaction between these is typical – for
    example both cyclic nucleotides and IP3 can
    trigger release of Ca++
           G-protein Coupled Receptors
• G-Protein coupled receptors,
  also known as 7-transmembrane
  or serpentine receptors
  because 7 a-helices pass
  through the membrane, are the
  largest family of transducer
  proteins, and the largest family
  of proteins known. The human
  genome codes for at least 90 G-
  proteins.
• Ligands for the GPCR range
  from photons through small
  transmitters to protein signaling
  molecules of the immune
  system.
• GPCR’s are targets for 40-50%
  of medicinal drugs
A generalized picture of the G-Protein-linked or
          G-Protein-coupled receptor
 G Proteins: αβγ = alpha, beta, gamma subunits
• G Proteins are molecular switches whose on or off
  state depends on whether GDT or GTP is bound to
  the α subunit. (A smaller monomeric G protein is called Ras
  and is associated with tyrosine kinase receptors that mediate
  cell growth and movement.)
• The G protein moves away from the receptor when
  GTP binds, and α dissociates from βγ (which are
  permanently linked). Both pieces of the G protein can
  interact with messenger systems, although in many
  cases the βγ subunit’s roles are not known.
• When Gα locates its target, the process of activating
  the enzyme causes hydrolysis of GTP, leaving GDP,
  and then the αβγ subunits must reunite. This
  terminates the active response to the ligand.
G-Protein Activation
 G Proteins: One possible target of G protein signal cascades is
adenyl cyclase, the enzyme that catalyzes the formation of cyclic
                              AMP
  Formation of cyclic AMP: the cyclic AMP is
destroyed by phosphodiesterase, yielding AMP
Different G-protein families are coupled
 to different 2nd messenger pathways
 • Gi inhibits the operation of adenyl cyclase
 • Gs stimulates the operation of the same
   enzyme
 • Gq stimulates phospholipase C, resulting in
   formation of inositol trisphosphate (IP3)
   and diacylglycerol (DAG) from a common
   membrane phospholipid, inositol
   bisphosphate.
Summary: Comparison of Ionotropic and Metabotropic receptor activity:
     metabotropic pathways can either open or close channels
Now to the muscarinic receptors
• Muscarinic receptors are characteristically found
  on targets for the parasympathetic division of the
  autonomic nervous system
• 5 subtypes M1-M5 have been identified
  genetically, but at present pharmacologists can
  distinguish only 4 subtypes.
• The subtypes differ in their locations in the body,
  their effects (excitatory vs inhibitory) and the
  particular G-proteins and 2nd messenger
  systems they are coupled to.
All muscarinic receptors are coupled to one
    of two main 2nd messenger systems
M1   Salivary glands,      Gq coupled to phospholipase C: inositol
     stomach, CNS          trisphosphate and diacylglycerol; increases
                           intracellular Ca++

M2   Heart, CNS            Gi coupled to inhibition of adenylyl cyclase,
                           decreased cAMP


M3   Blood vessels, eye,    Gq coupled to phospholipase C: inositol
     visceral smooth       trisphosphate and diacylglycerol
     muscle, lung airway

M4   CNS                   Gi coupled to inhibition of adenylyl cyclase,
                           decreased cAMP

M5   ?                     Gq coupled to phospholipase C: inositol
                           trisphosphate and diacylglycerol
 Muscarinic receptors are targets for many drugs
    and toxins – only a few are shown here

• M1: carbachol, atropine, scopolamine,
  mambatoxin MT7
• M2: methachol, carbachol, atropine
• M3:, carbachol, methachol, atropine
• M4: bethanechol, carbachol, atropine,
  mambatoxin MT3

  Agonists are shown in black; antagonists in red
         Adrenergic receptors
• Adrenergic receptors are found on the targets of
  the sympathetic division of the autonomic
  nervous system.
• The transmitter released at sympathetic
  synapses is norepinephrine (noradrenaline);
  the sympathetic hormone released by the
  adrenal medulla is epinephrine (adrenaline) –
  these are catecholamines.
• There are 2 families of adrenergic receptors,
  alpha and beta.
• There are 2 subgroups of alpha receptors and 3
  of beta receptors
          Gi
          coupled




                    Gs
Gq                  coupled
coupled

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:3
posted:9/10/2012
language:English
pages:30