signal transduction and receptor pharmacology Flashcards
(37 cards)
1
Q
morphology of the neuromuscular junction
A
- myelin sheath ends, leaving a bare nerve terminal
- nerve terminal contains synaptic vesicles and mitochondria, which cluster around active zone
- active zone is aligned with a junctional fold in the muscle, containing nicotinic acetylcholine receptors
- fibrous matrix between nerve and muscle contains acetylcholinesterase
2
Q
end plate potential
A
local muscle depolarization produced by release of Ach
3
Q
pre-synaptic processes of the skeletal NMJ
A
1 AP => ACh released from ~100 vesicles
- Ach containing vesicle is tethered to the nerve ending membrane via the SNAREs of the fusion machine
- depolarization caused by nerve AP opens voltage gated Ca2+ channels on the presynaptic neuron membrane
- Ca2+ travels down its electrochemical gradients, entering the nerve ending and binding synaptotagmin Ca2+ sensor on the fusion machine
- Conformational change induced by Ca2+ binding causes SNARE primed vesicle to release NT contents via exocytosis
4
Q
post-synaptic processes of the skeletal NMJ
A
- Ach diffuses across 40 nm synaptic cleft and reacts with its nicotinic receptor (ligand gated, non-selective cation channel)
- Very rapidly, the non-selective cation channel opens
- Na+ flows down its electrochemical gradient into the cell, depolarizing the end plate membrane
- The end plate potential generates a muscle action potential which propagates along the muscle causing contraction
- AChE degrades ACh and terminates its activity
5
Q
Tetrodotoxin (TTX) pharmacology
A
- compound found in pufferfish
- inhibitor of somatic PNS
- blocks voltage gated Na+ channels
- prevents initiation of APs in nerves (pre-NMJ) AND in skeletal muscle (post-NMJ)
6
Q
Mg2+ and polyvalent cation pharmacology
A
- inhibitor of somatic PNS
- compete with Ca2+ at the pre-NMJ Ca2+ channel
- reduce ACh release by reducing Ca2+ sensing
7
Q
Aminoglycoside (side effect) pharmacology
A
- inhibitor of somatic PNS
- reduce Ca2+ entry through pre-NMJ Ca2+ channel
- reduced ACh release
8
Q
Botulinum toxin type A pharmacology
A
- inhibitor of somatic PNS
- from clostridium botulinum
- cleaves the SNARE SNAP-25, preventing the priming of ACh release machinery
- prevents ACh release
- used to treat spasticity
9
Q
Tubocurarine pharmacology
A
- inhibitor of somatic PNS
- south american indian arrow poison
- competitive inhibitor of ACh at nicotinic receptors at the NMJ
- non-depolarizing blocker
10
Q
“-curonium” drug (rocuronium and vecuronium) pharmacology
A
- inhibitor of somatic PNS
- competitive inhibitor of ACh at nicotinic receptors at the NMJ
- non-depolarizing blocker
- used to relax skeletal muscle in surgery
11
Q
succinylcholine (SUX) pharmacology
A
- inhibitor of somatic PNS
- inhibits nicotinic receptors AFTER depolarizing the muscle
- depolarizing blocker
- rapid action => used to relax skeletal muscles for intubation
12
Q
myasthenia gravis
A
- nicotinic receptors of the somatic PNS are destroyed by circulating antibodies
- patients readily fatigued
13
Q
neostigmine pharmacology
A
- reversible AChE inhibitor => enhances synaptic transmission
- speeds recovery from a non-depolarizing block after surgery
- used to treat myasthenia gravis
14
Q
sarin pharmacology
A
- irreversible AChE inhibitor => enhances synaptic transmission => nerve gas
15
Q
structural elements of the ANS
A
- preganglionic nerve fibers with cell bodies in CNS
- autonomic ganglia = site of neuro-neuronal synapse outside CNS; receptors here are nicotinic
- postganglionic nerve fibers with cell bodies in the autonomic ganglia
- neuroeffector junction = post-ganglionic nerve terminals synapsing with effector organs = targets for clinically used drugs!!
16
Q
structural differences between the parasympathetic and sympathetic divisions of the ANS
A
- parasympathetic neurons synapse close to the effector organ; sympathetic neurons synapse at the chain ganglia (close to spinal cord)
- parasympathetic system has muscarinic cholinergic (ACh) receptors; sympathetic system has alpha and beta adrenoreceptors (NE)
17
Q
anatomical differences between sympathetic and parasympathetic divisions of the ANS
A
- sympathetic: preganglionic fibers emerge from thoracic and lumbar regions of the spinal cord
- parasympathetic: preganglionic fibers emerge from cranial and sacral regions
18
Q
chemical synaptic transmission in the ANS (relative to the skeletal NMJ)
A
very similar to cholinergic transmission in the skeletal NMJ except:
- NT is norepinephrine
- NE action is terminated by reuptake into nerve terminal by a solute carrier
- receptors are a-1 and b-1 adrenoreceptors (GPCRs)
19
Q
2 signal transduction pathways of the parasympathetic division of the ANS
A
- membrane delimited GPCR signalling
2. synthesis of 2nd messengers via PLC stimulation (no ~P)
20
Q
Parasympathetic slowing of the heart
A
via membrane delimited GPCR signalling (FAST: 30-50 ms)
- ACh binds muscarinic GPCR
- beta and gamma subunits activate K+ channels
- membrane is hyperpolarized and excitation inhibited => heart slows
21
Q
Atropine
A
- antagonist of parasympathetic ANS
- competitive inhibitor of ACh at muscarinic receptors
- increases heart rate by blocking ACh induced slowing
22
Q
Parasympathetic constriction of the airways
A
via synthesis of 2nd messengers by PLC stimulation
- ACh binds muscarinic GPCR
- GDP -> GTP exchange
- alpha subunit stimulated PLC
- PIP2 forms IP3
- IP3 acts via the water soluble limb of the pathway to initiate Ca release from the ER
- smooth muscle contraction
23
Q
Atropine derivatives (ipratropium, tiotropium)
A
- antagonist of parasympathetic ANS
- competitive inhibitors of ACh at muscarinic receptors
- open airways by block ACh induced constriction
24
Q
3 signal transduction pathways of the sympathetic ANS
A
- synthesis of 2nd messengers (no ~P)
- synthesis of 2nd messengers and ~P of b-1 and b-2 receptors
- membrane delimited GPCR signalling
25
Sympathetic vascular constriction
via synthesis of 2nd messengers
1. NE binds alpha-1 adrenoreceptor
2. GDP -> GTP exchange
3. alpha subunit activates PLC
4. PIP2 forms IP3
5. IP3 acts via the water soluble limb to initiate Ca release from the ER
6. vascular smooth muscle contraction
26
Norepinephrine (drug)
- agonist of the alpha-1 (and beta) adrenoreceptor of the sympathetic nervous system
- increases BP via smooth muscle contraction
27
Phenylephrine
- selective agonist of the alpha-1 adrenoreceptor of the sympathetic nervous system
- increases BP and decreases nasal constriction via smooth muscle contraction
28
Sympathetic cardiac stimulation
via synthesis of 2nd messengers with phosphorylation (slower: minutes)
1. NE binds b-1 adrenoreceptor GPCR
2. alpha subunit stimulates adenylyl cyclase
3. increase in cAMP => increased intracellular Ca2+
4. PKA activation => phosphorylation
5. cardiac stimulation
29
metoprolol
- competitive inhibitor of NE selectively at the b-1 receptors in the heart
- used to treat arrhythmias and hypertension
30
propranolol
- competitive inhibitor of NE at b-1 and b-3 receptors
| - used to treat arrhythmias and hypertension
31
Sympathetic smooth muscle relaxation
via synthesis of 2nd messengers with phosphorylation
1. NE binds b-2 adrenoreceptor GPCR
2. alpha subunit stimulates adenylyl cyclase
3. increase in cAMP => decreased intracellular Ca2+
4. PKA activation => phosphorylation
6. smooth muscle relaxation
32
"-erols": albuterol, salmeterol, formoterol
- selective beta-2 agonists
| - relax bronchiolar smooth muscle and open airways
33
General inhibition of cell excitability in the sympathetic system
via membrane delimited GPCR signalling generic inhibitory motif:
1. alpha-2 agonist (NE or EPI) binds alpha-2 receptor
2. downstream inhibitory effects:
- beta and gamma subunits activate K+ channels => depolarization
- beta and gamma subunits activate Ca2+ channels => depolarization
- alphai subunit inhibits adenylyl cyclase, decreasing CAMP
34
how are blood pressure and blood vessel radius related?
BP inversely proportional to the 4th power of the blood vessel radius
35
Poiseuille's law
total peripheral resistance = constant / pi*r^4
36
equation for BP
BP = cardiac output x total peripheral resistance
CO = HR x stroke volume
37
epi vs norepi
- epi activates all adrenergic receptors (a1, a2, b1, b2) while norepi has no effect on b2
- smooth muscles contain b2 receptors that are not innervated (don't respond to norepi) but can respond to circulating epi
