1-57 Signal Transduction in Nervous System Flashcards
(28 cards)
General scheme for autonomic nervous system signaling
Skeletal Muscle Ach signal release scheme
SNAP-25
- Protein that tangles with vesicle snares and plasma membrane snares to make the snare bundle and hold vescile near the membrane
- Calcium sensor binds the bundle to link vesicle release to intracellular calcium increase
- SNAP-25 is target for botulinum toxin
Relevant toxins in nerve signal propagation
- Tetrodotoxin:
- blocks Na+ channels on the presynaptic nerve terminal on the extracellular side to plug and prevent Na+ influx to propagate AP
- Also blocks Na+ influx on post-synaptic muscle cell
- Mg+2 (etc.), other polyvalent cations
- Inhibit Ca+2 channels influx into cells
- Aminoglycoside antibiotics also inhibit Ca+2 influx
- Botulinun toxin:
- Cleaves SNAP-25 part which prevents vesicle/membrane fusion and calcium sensing, so no vesicle release!
Nicotinic AcH Recpetor Blockers
- Curonium (rocuronium, vecuronium): non-depolarizing blockers to relax skeltal muscle during surgery, competitive inhibitor
- Succinylcholine: depolarizing blocker, depols cell before it blocks, used to relax skeletal muscle for intubation because super rapid and cholinesterase will degrade so you can administer an “overdose”
Myasthenic Gravis
- Antibodies destroy postysynaptic nicotinic receptors
- initial muscle strength may be normal BUT NMJ readily fatigues
- many less Nicotinic receptors on post-synaptic muscle cell so unable to fire as often
Cholinesterase inhibitors
- inhibit the degredation of ACh by cholinesterase
- therefore, more Ach in the synaptic cleft for longer and can send stronger signals
- NeoSTIGMINE: reversible cholinesterase inhibitor used to speed recovery from rocuronium/vecuronium after surgery
- used to treat Myasthenia Gravis
Sarin
- irreversible inhibitor, nerve gas
- cholinesterase inhibitor, makes Nicotinic channels go haywire
General scheme for autonomic nervous system signaling
Adrenal medulla general signaling scheme
- Epinephrine: can activate all catecholamine receptors (a1, a2, b1, b2)
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Sympathetic vs. Parasympathetic
Sympathetic:
- pre-ganglionic origins: thoracolumbar
- Synaptically: NE not degraded by cholinesterase (obviously) it is taken back up into nerve terminal (SLCs)
- post-synaptic receptor: Norepepinephrine signals on to Alpha1 or Beta1 GPCRs (on smooth or cardiac muscle)
Parasympathetic:
- pre-ganglionic origins: cranial-sacral
- post-synaptic receptor: ACh signals on to muscarinic GPCR
Parasympathetic signaling in heart
- ACh released by vagal stimulation slows the heart and slows cardiac conduction
- Binds muscarinic ACh receptors of SA node
- GPCR activated and beta-gamma subunit activated K+ channels
- K+ goes out of cell and hyperpolarizes to reduce heart rate and cardiac conduction
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Atropine: drug, competitive inhibitor at the Muscarinic receptors on SA node, will block parasympathetic input and keep heart rate high
- used during spinal surgeries to be able to numb lower body but keep heart rate up
Atropine
Atropine: drug, competitive inhibitor at the Muscarinic receptors on SA node, will block parasympathetic input and keep heart rate high
Parasympathetic effect on airways?
- Ach signals on to Muscarinic receptors in bronchioles
- Activated GPCR->GTP-alphaQ activates PLC->activated IP3->Ca+2 release from ER->constricts
- Drugs: atropine derivatives: iprATROPIUM, tioTROPIUM
- competitive inhibitors of ACh at muscarinic receptors
-ATROPIUM, -TROPIUM
atropine derivatives: iprATROPIUM, tioTROPIUM
competitive inhibitors of ACh at muscarinic receptors
used to treat asthma, COPD
Sympathtic signaling on smooth muscle vessels
- NE released from sympathetic nerve endings onto alpha-1 receptors
- GPCR of alpha1R->GTP-alphaQ activates PLC->IP3->Ca+2 release->constricts vessel
Norepinephrine, phenylephrine mechanism in smooth muscle vessels
Epinephrine effect on heart
Increases in cAMP in cardiac vs. smooth muscle
Cardiac: increase cardiac contractility, Beta1 receptors
- increase cAMP->increased L-type Ca+2 channel activity/Ca+2 entry->increased contratility and increased sarcoplastic reticulum Ca+2 stores
Smooth muscle: inhibit smooht muscle contration, Beta2 receptors
- increased cAMP->reduces calcium entry and/or increases calcium removal->decreases contractility
Dependent on the activated PKA downstream phosphorylation targets
Propranolol/Metoprolol
-OLOLs: competitive inhibitors of NE at beta-1 receptors in the heart
- propranolol: inhibits b1 and b2
- metoprolol: inhibits ONLY b1, so that b2 in lungs still working, use this drug in asthmatics
Albuterol, salmeterol, formoterol
EROLs: beta2 agonists, relax smooth muscles in airways
alpha2 receptors
- activation causes membrane delimited gbeta/gamma sununits to activate or inhibit ion channels, follows the inhibitory motif (2 inhibits, 1 or 3 activates)
- Clonidine: agonist of alpha2, to treat hypertension
- NE and Epi are also agonists of alpha2 receptors
Sympathetic tone
- tonic vasoconstriction due to the tonic firing of SYMPATHETIC NERVES innerating vasculature
- blood vessel are largely devoid of PARASYMPATHETIC innervation
- Major determinant of BP: radius of blood vessels
Blood pressure equations
Blood Pressure = Cardiac output x total peripheral resistance
Cardiac output = Heart rate x stroke volume
Total peripheral resistance = stuff / pi blood vessel radius^4
THEREFORE: changing radius of blood vessel is the most significant factor to effect BP
