Catapult Pharmacology
Neurotransmitters & Signaling Part 2: Adrenergics and Receptors
Neurotransmitters and Signaling: Norepinephrine and Epinephrine
Norepinephrine is released by exocytosis in response to signals from the postganglionic neuron at the nerve terminal to effector organs in the sympathetic nervous system (SNS).
After exocytosis norepinephrine has 4 destinations:
Activation of the postsynaptic receptor.
Reuptake into the presynaptic neuron (recycled or metabolized by monoamine oxidase (MAO).
Metabolized by Catechol-O-methyltransferase (COMT).
Activation of the post-synaptic receptor (negative feedback).
Norepinephrine and epinephrine are also released from the adrenal medulla as hormones into the general circulation.
Norepinephrine and Epinephrine Synthesis
Tyrosine hydroxylated by tyrosine hydroxylase to form dihydroxyl phenylalanine (dopa).
Dopa is then converted to dopamine by dopa decarboxylase.
Dopamine is bound into vesicles and converted to norepinephrine by dopamine-beta-hydroxylase
Norepinephrine is converted by phenylethanolamine-N-methyltransferase to create epinephrine (mostly in adrenal medulla).
Adrenoreceptors
Adrenoreceptors are primarily found in the effector organs of the sympathetic nervous system. There are two types of adrenoceptors - alpha and beta. Each type of receptor binds epinephrine and norepinephrine. See the tables below for important characteristics of each receptor subtype.
Alpha Adrenoreceptors
| Receptor Type | Physiologic Response | Signal Transduction |
|---|---|---|
| α1 | GI Relaxation; Mydriasis (pupillary dilatation); Vasoconstriction; - ↑ PVR; - ↑ BP; ↑ Bladder sphincter tone | Gq, activated. Results in IP3 (Calcium influx) and DAG (PKC activation) release |
| α2 | ↓ Norepinephrine release; ↓ Insulin release; ↓ Lipolysis; ↓ Aqueous humor production; ↓ ACh release | Gi, g-protein linked receptor, which inhibits adenylyl cyclase, which decreases cAMP levels |
Beta Adrenoreceptors
| Receptor Type | Physiologic Response | Signal Transduction |
|---|---|---|
| β1 | ↑ Chronotropy; ↑ Inotropy; ↑ Lipolysis; ↑ Renin release | Gs, Activates adenylyl cyclase, increasing cAMP levels |
| β2 | Vasodilation; - ↓ PVR; Bronchodilation; Mobilizes glucose; - ↑ Glycogenolysis; - ↑ Glucagon release; ↓ Uterine tone | Gs, Activates adenylyl cyclase, increasing cAMP levels |
| β3 | ↑ - Lipolysis; Bladder relaxation | Gs, Activates adenylyl cyclase, increasing cAMP levels |
Desensitization
Desensitization of the receptors occurs with prolonged exposure to catecholamines. Proposed mechanisms include decreased availability of receptors and disruption of the ability of the receptor to couple with the G-protein.