L9 Desensitisation and Ion Channel Receptors Flashcards
Desensitisation
Response to a drug decreases when taken continuously or repeatedly
Response may be restored by increasing the dose.
Tachyphylaxis (Desen)
- response to drug diminishes rapidly
- neurotransmitter depletion and receptor phosphorylation
Tolerance (Desen)
- Response decreases over days or weeks
- decreased receptor number and physiological changes
- longer than tachyphylaxis
Desen mechanisms
Change in receptors
Receptor translocation
Exhaustion of mediators
Altered drug metabolism
Physiological adaptation (homeostasis)
Active extrusion from cells (cancer chemotherapy)
Desen mech: Change in receptors
ion channel receptors display rapid desen and it causes a conformational change in receptors
*If taken continuously (acetylcholine) there is a sustained response that diminishes overtime
* if taken once there is a big spike in response.
* receptor phosphorylation
Desen mech: Exhaustion of mediators
Similar to tachyphylaxis - depletion of a mediating substance decreases the effect.
amphetamine releases noradrenaline from nerve terminal in place of noradrenaline which become depleted → no NoraA there is no NT it became desensitised
Desen mech: Altered drug metabolism
Increase metabolism of ethanol and barbiturates results in lower plasma concentration
– Metabolism occurs quickly and reduces the effect of drugs because of lower plasma drug levels
Enzymatic induction and increased drug metabolism
Increased hepatic enzyme pathway capacity increases metabolism and lowers plasma concentration.
Decreased metabolism of a prodrug can result in a reduced effect.
Desen mech: Physiological adaptation (homeostasis)
- Thiazide diuretics lower blood pressure (treats BP and increases urine flow)
- Limited by activation of renin-angiotensin system
Desen mech: Active extrusion from cells (cancer chemotherapy)
If extruded then its desensitised and no longer active
4 receptor superfamilies
*Ion channels (VERY FAST)
*G protein coupled receptors (FAST)
-change in membrane excitability
-generation of second messengers
-protein phosphorylation
*Enzyme linked (SLOW)
- protein phosphorylation, gene transcription, protein synthesis
*Nuclear (DNA linked, intracellular) (VERY SLOW)
- gene transcription and protein synthesis
Major types of ion channels
- Ion channel receptor- ligand-bind reg opening/closing
- Voltage gated ion channel - change in potential or V-gradient regulates channel opening and ion conductance
- Second messenger-regulated ion channel - ligand binding to g protein coupled receptor leads to second messenger generation it also regulates opening and ion conductance
Ion channels
penetrate membranes?
internal potential?
action?
Ions cannot cross membrane
-30 to -80 at resting conditions
Open and close to regulate flow - depolarisation/hyperpolarization
– play role in neurotransmission, cardiac conduction, muscle contraction and sections
Membrane potentials
Depend on balance of ions in/out-side of cell
Neg: Cl
Pos: Na, K, Ca2+
Ion channels characterised by
- selectivity of ion species
- pore size and lining
- cations and anions
- gating properties (controls opening and closing)
- Structure
The rate and direction of movement in an ion channel depends on
the electrochemical gradient and membrane potential
Patch clamp recording
Measures flow of ions through a channel
- Flow of current through a single open channel is in pA (picoamp = 10-12 amps)
- Agonist binding causes repeated channel openings (graph on slides)
Patch clamp record
Ion channel activity is characterised by
- ion currents
- freq of channel openings
- different agonists cause different frequencies of channel opening
Ion channel receptors subunits how many and where
- 4-5 membrane spanning subunits
- both intra and extra- cellular regions
- membrane spanning section
Can ions cross membrane when channels are closed
no
protein subunits that make up an ion channel receptor
alpha
beta
gamma
delta
The composition determines the properties.
Typical ion channel receptor subunit structure - draw it
- 4 membrane spanning alpha helices
- amino and carboxyl ends both extracellular
- binding domain.
Ligand binding example
Nicotinic acetylcholine receptor
Ligand binding channel open
When two agonist molecules bind to two alpha subunits to cause channel opening
- needed to activate receptor
- 5 subunits turn in relation to each other
- Then the channels open
Large number of different___ agonists activate ion channel receptors
endogenous
Endogenous agonists examples
- acetylcholine, g-aminobutyric acid (GABA)
- glycine, glutamate, 5-hydroxytryptamine (5-HT)
Activation causes what changes in cell membrane potential
depolarisation or hyperpolarisation
Changes in membrane polarisation produce____ changes in the target cell
biochemical
acetylcholine as an agonist example
Acetylcholine stimulates
* nicotinic acetylcholine receptors
* ion channel receptor acetylcholine
* depolarisation, excitatory response
* muscarinic acetylcholine receptors
Nicotinic acetylcholine receptors are found where
- skeletal neuromuscular junction
- ganglion cells in the peripheral nervous system
- neurons in the central nervous system
Muscarinic acetylcholine receptors are what type
G protein-coupled receptor
When sodium ions enter a cell membrane it causes which change
depolarisation
acetylcholine will cause sodium influx
the causes depolarisation and fire an action potential for muscle cell contraction
Agonists: g-aminobutyric acid (GABA)
- GABA is formed from glutamate in the brain
- GABA is an inhibitory transmitter in many central nervous system pathways
- Cause Hyperpolarisation
GABA is formed from what in the brain
glutamate
GABA is an ____ transmitter in many (CNS or PNS) pathways
inhibitory
CNS
What change in cell potential does BAGA cause
Hyperpolarisation
3 types of GABA receptor
- GABA(A) and (GABA(C)) – ion channel receptors
- GABA(B) – G protein-coupled receptor
Agonists: glycine
(endogenous ligand)
- amino acid – stimulates glycine receptors
- inhibitory neurotransmitter mainly in the spinal cord ->hyperpolsation (-)
- strychnine – surmountable antagonist at glycine receptors
- strychnine - convulsions and muscle contraction
Agonists: glutamate
- amino acid – stimulates glutamate receptors
- fast acting excitatory neurotransmitter in the CNS
- Depolarises (+)
Agonists: 5-hydroxytryptamine (5-HT, serotonin)
- many actions including increase gastrointestinal motility, vasodilation, platelet aggregation
- agonist at different receptor types including ion channel receptors in the nervous system
Strychnine
– surmountable antagonist at glycine receptors
- convulsions and muscle contraction
Will bind to glycine receptors to prevent gly from bindto and therefore prevent inhibition actions.
GABAA receptors are ionotropic receptors that allow for chloride ions to flow into a cell upon agonist (GABA) binding. What do the Cl ions do?
Chloride ions moving into a cell typically decrease second messenger signaling and produce inhibitory effects.
Neuromuscular junction location
Between nerve and skeletal muscle fibre. In an adult 1 motor neuron can activate each skeletal muscle fibre.
Neuromuscular junction signal pass (NJ1)
Signals pass along motor nerve to presynaptic boutons. The structure will increase surface area across which the neurotransmitter can be release (slide 22)
Muscle fibre pre or post -synapse
Post
Skeletal nerve will release (NJ2)
Acetylcholine which crosses the synaptic cleft and interacts with nicotinic acetylcholine receptors on the muscle.
Myelin
Insulation to speed up the impulse
Impulse will move down the motor nerve and (NJ3)
synaptic vesicles that contain the NT (acetylcholine) move towards the membrane. Then release acetylcholine into the synapse to move across the synaptic cleft. Some will go across and bind to activate nicotinic Ach receptor on skeletal muscle.
Nicotinic acetylcholine receptor
5 subunits and requires two molecules of acetylcholine [ACh] to bind to open the channel (has two binding sites)
Nicotinic acetylcholine receptor open
When two Ach bind to the sites the channel opens at the gate and sodium (+) enters the cell along a conc gradient.
Sodium moves along a conc. gradient to do what to a cell
– depolarisation of nearby cell membrane
Does an ion channel receptor stay open
No - there are repeated channel openings
What to repeated ion channel openings trigger
Nearby voltage-gated ion channels to open
Voltage-gated ion channels when open:
- greater influx of Na+ ions
- widespread depolarisation
- if depolarisation reaches threshold, muscle contracts
pancuronium is a what type of antagonist
- Surmountable antagonists
Surmountable antagonists (pancuronium) will bind to Nicotinic Ach receptors to prevent Ach from binding causing what
- bind to receptor, but not open the channel
- compete with acetylcholine
- skeletal muscle paralysis
- adjunct to anaesthesia -> prevent muscle twitching in surgery
Long-acting agonists (suxamethonium)
- bind to ion channel receptor, channel remains open
- prevent repetitive depolarisations required for voltage-gated channels to produce sustained contraction
- neuromuscular block
- short-acting muscle relaxant
- short term paralysis e.g., tracheal intubation
GABAA receptor location and what type
- GABA is a chemical messenger found at synapses throughout the brain
- GABAA receptor is an example of an ion channel receptor with an inhibitory response
- similar to Nico Ach receptor except Cl- ions enter the cell
GABAA receptor structure similar to what.
- The GABAA receptor has a similar structure and function to the nicotinic acetylcholine receptor
- except Cl- ions enter the cell
GABA is released from where
presynaptic neuron
GABA releases and crosses what to do what
- crosses synaptic cleft
- binds to GABAA receptor a-subunits
- channel opens
- Cl- ions move into the cell
Influx of negatively charged Cl- ions by GABA causes what
the postsynaptic cell to become hyperpolarised
- Activation of GABAA receptors has a what effect on CNS neurons
inhibitory
Control of blood glucose levels after a meal tissue response
agonist: insulin
Receptor: enzyme - slow
Dilation of airways in the lungs to adrenaline tissue response
beta2-adrenoreceptors
g-protein coupled - fast
Protein synthesis cause by hydrocortisone
Nuclear receptors
Very slow
Response of the brain to an emergency situation
Ion channel
Very fast
Twitch of skeletal muscle in response to Ach
Ion channel - nicotinic Ach receptor
Very fast
Change in receptor morphology as desensitisation mech
Can occur with ion-channel receptors and GPCRs:
*Ion-channel receptors bind the ligand but do not open the channel
*GPCR become ‘uncoupled’ - phosphorylation of the receptor makes it unable to activate second messenger cascade, though it can still bind the ligand.
