Lecture 6 - PNS/Adrenergic Receptors Flashcards
Adrenal medulla?
Major organ of sympathetic NS, secretes lots of adrenaline (little NE).
Chromaffine storage cells - preganglionic sympathetic fibres release Ach and act on nAchR –> chromaffin storage depolarisation and influx of Ca2+ through VG Ca2+ channels. Ca2+ triggers exocytosis of chromaffin granules and thus release adrenaline into blood stream.
Noradrenaline synthesis in sympathetic neurones?
TYROSIN transported into sympathetic nerve axon –> converted to DOPA by TYROSINE HYDROXYLASE –> converted to DOPAMINE by DOPA CARBOXYLASE –> transported into vesicles, converted to NORADRENALINE by DOPAMINE-B-HYDROXYLASE.
Action potential –> depolarises and Ca2+ enters axon –> increase [Ca2+] causes vesicles to migrate to axonal membrane and fuse. NE –> extracellular space –> binds post junctional receptor and stimulates organ (effector) response.
Adrenaline synthesis in adrenal medulla?
NORADRENALINE –> ADRENALINE by PHENYLETHANOLAMINE-N-METHYL TRANSFERASE in adrenal medulla.
Sympathetic pre-gang fibres release Ach –> binds post junctional nicotinic receptors –> leads to adrenaline synthesis in adrenomedullary cells. Additional enzyme (PNMT) adds methyl group to NE molecule –> adrenaline. Released into blood perfusing the glands and carried throughout body.
Adrenergic receptor classification?
Two main classes (a and b) - based on potency profiles for adrenaline/noradrenaline and isoprenaline. Further divided into 3 a1, 3 a2 and 3 b receptors (based on molecular biology).
Differentially expressed in tissues and regulate diverse physiological responses.
Physiological functions of alpha adrenoreceptors?
a1 - activates PLC –> IP3 + DAG (via Gq) - generally post synaptic, results in contraction in SMCs due to increase in [Ca2+]. Causes relaxation of gut due to contraction of circular muscle.
a2 - inhibits adenylate cyclase –> decrease in cAMP production (via Gi) - generally presynaptic, inhibits release of noradrenaline from post ganglioninc neurone (-ve feedback loop).
Physiological functions of beta adrenoreceptors?
ALL ACTIVATE ADENYLATE CYCLASE –> increase cAMP (via Gq)
b1 - stimulation by adrenalne –> +ve chronotropic and inotropic effect on heart and increased conduction velocity and automaticity. In kidney causes renin release.
b2 - induces smooth muscle relaxation, induces tremor in skeletal muscle + increases glycogenolysis in liver and skeletal muscle.
b3 - induces lipolysis in fat cells.
a2 in the heart?
Presynaptic a2 receptor stimulation decreases noradrenaline release. cAMP usually acts to promote Ca2+ influx in response to membrane depolarisation –> increased noradrenaline and ATP release.
Evidence that presence of facilitatory b2 adrenoreceptors on pre-synaptic terminal may stimulate NE release (WENDELL, 2004).
Normal process in heart in absence of B-adrenergic stimulation?
- LTCCs open –> activates RyR –> CICR from SR –> contraction. Ca2+ reuptake by SERCA.
- RyR and SERCA attenuated by interaction with FKBP and PLB respectively - only work when they are not phosphorylated (i.e. when PKA is inactive)/
Overall effect = decreased rate of muscle relaxation and contractility –> decreased HR and SV.
Stimulation of B1 in the heart?
B1 (couple to Gs protein –> increased cAMP) –> activates cAMP depenent PKA, which phosphorylates mutltiple targets.
- LTCCs - increased Ca2+ entry into cell.
- FKBP - inhibits its interaction with RyR –> RyR is more active. Net result is increased Ca2+ entry during APs and enhanced Ca2+ release by SR –> more calcium binding troponin C –> POSITIVE INOTROPIC EFFECT
- PLB - inhibits interaction with SERCA, resulting in SERCA being mor active. Net result is enhanced uptake of Ca2+ into SR - increased rate of relaxation (POSITIVE CHRONOTROPC EFFECT).
a1 in blood vessels?
Stimulation –> PLC –> IP3 –> Ca2+ release from SR. Binds calmodulin and activates it –> activates myosin light chain kinase (MLCK) –> phosphorylates myosin light chain. MLC interacts with actin to form actin-myosin cross bridges –> initiates vascular contraction.
CALMODULIN = multifunctional intermediate messenger protein that transduces calcium signals by binding Ca2+ and modifying its interactions with proteins.
b2 in blood vessels?
Stimulation –> *AC –> cAMP –> *PKA, which phosphorylates target proteins and the following happens:
- INCREASED SERCA ACTIVITY - resultng in Ca2+ being stored in the SR.
- INCREASED PMCA* ACTIVITY - resulting in Ca2+ being transported outside the cell.
NET RESULT = decreased Ca2+ conc –> decreased activation of MLCK –> SM relaxation. - DECREASED MLCK AFFINITY FOR Ca2+-CaM BINDING - through direct phosphorylation.
NET RESULT = decreased MLCK activity –> decreased MLC phosphorylation –> SM relaxation.
Clinical uses of beta agonists?
Salbutamol - (B2 agonist) - for asthma
Adrenaline - (a/b agonist) - asthma, anaphylaxis, cardiac arrest.
Clinical uses of alpha-1 blockers?
DOXAZOSIN, PRAZOSIN, TERAZOSIN
Treatment of hypertenson. Inhibit peripheral vasomotor tone by blocking post-synaptic a1 receptors -> decreased vasoconstriction and systemic vascular resistance.
Clinical uses of non-selective alpha-adrenergic antagonists?
PHENOXYBENZAMINE, PHENTOLAMINE
Used in short term management of phaeochromocytoma (rare catecholamine secreting tumour derived from adrenal chromaffin cells - catecholamine release not precipiated by neural stimulation - mechanism unclear. Secrete noradrenaline predominantly, whereas normal tissue secretes 85% adrenaline).
Result is reflex tachycardia due to inhibition of presynaptic a2 adrenergic receptor. Can be controlled by careful titration of cardioselective beta-blocker. NOT GOOD for treating hypertenson due to tachycardia, cardiac dysrhythmias and increased GI activity.
Clinical uses of B-adrenergic receptor blockers?
PROPANOLOL, ATENOLOL, TIMOLOL, BISOPROLOL…
Angina, hypertension, tachyarrhythmias and HF.
Block effect of sympathetic nerve distribution or circulating catecholamines at B-adenoreceptors.
Predominant in heart + kidney (B1) and lung, liver, GI tract, blood vessels and skeletal muscle (B2).
