1-57 Signal Transduction in Nervous System Flashcards
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
Receptors on blood vessels? (2)
- alpha1: innervated from sympathetic nerve, fires NE, vasoconstrict
- beta2: no innervation but systemic EPI released from adrenal medulla, fires, vasodilate
Summary of innervation and receptors of heart
Summary of innervation and receptors of blood vessels
Summary of innervation and receptors of lung bronchioles
