Adrenal medulla and catecholamines

adrenal medulla

produces catecholamines epinephrine (80% in humans; varies across species) and norepinephrine

autonomic nervous system

not under conscious control, maintain homeostasis

sympathetic nervous system

• most active during stress or physical activity

• preganglionic neurons exit central nervous system via thoracic & lumbar spinal nerves; secreted neurotransmitter is acetylcholine (cholinergic)

• autonomic ganglia (cluster of nerve cell bodies in autonomic nervous system) usually close to spinal cord

• postganglionic neurons: primary secreted neurotransmitter is norepinephrine

parasympathetic nervous system

• most active during rest

• preganglionic neurons, exit central nervous system via cranial & sacral spinal nerves; secreted neurotransmitter is acetylcholine (cholinergic)

• autonomic ganglia (cluster of nerve cell bodies in autonomic nervous system) usually close to target organs

• postganglionic neurons: Primary secreted neurotransmitter is acetylcholine (cholinergic)

enteric nervous system

innervates organs of gastrointestinal system

which nervous system is adrenal medulla a part of

the sympathetic nervous sytem

what are adrenal medullary cells

chromaffin cells

chromaffin cells

• large columnar cells (With lots of granules) Arranged around network of capillaries

• modified postganglionic nerves that lack axons, or modified sympathetic ganglion

• innervated by preganglionic fibers of sympathetic nervous system that release the neurotransmitter acetylcholine (“cholinergic nerves”)

• activation of nicotinic receptors (In superfamily of ligand gated ion channel receptor) causes cell depolarization & influx of Ca2+ through voltage dependent calcium channels

• in response, chromaffin cell secrete their products, but into extracellular space/circulation, instead of into a synapse

• contents include catecholamines (epinephrine & some norepinephrine) that bind to adrenergic receptors on target organs; also many other secreted contents, include various neuropeptides

what are catecholamines

organic compound that has a catechol (benzene ring with 2 adjacent hydroxyl group) + a side chain with an amine group

what are catelcholamines synthesized from

synthesized from the amino acid tyrosine by a process of hydroxylation & decarboxylation

what do catecholamines include

• dopamine (found in adrenal medulla & peripheral sympathetic nerves, but acts primarily as neurotransmitter in CNS; in circulation from gastrointestinal tract acts as a paracrine hormone)

• norepinephrine (synthesized & stored in adrenal medulla and also in peripheral sympathetic nerves)

• epinephrine (primary hormone/released by adrenal medulla into circulation)

catelcholamine synthesis

• tyrosine (from food or synthesized in liver from phneylalanine): actively transported into neurons & chromaffin cells

• tyrosine is converted to DOPA by tyrosine hydroxylase; enzyme is under regulator control (activity inhibited by high catechol level; transcription stimulated by glucocorticoids & by acetylcholine via nicotinic cholinergic receptor)

• decarboxylation of DOPA to dopamine, then dopamine is activately transported into granulated vesicles to be hydroxylated to norepinephrine

• only 7% of circulating norepinephrine is from adrenal medulla (most is from diffusion out of nonadrenal sympathetic neuronal synapses)

adrenergic receptors (adrenoreceptors)

• present in most cells of the body (variable distribution of receptor subtypes)

• bind adrenergic agonists such as sympathetic neurotransmitter norepinephrine and the circulating hormone epinephrine

g protein coupled receptors activated by norepinephrine & epinephrine

receptor groups and subtypes include a1, a2, b1, b2 & dopamine receptor subtypes classified as either delta 1 or delta 2 type

norepinephrine & epinephrine activate which receptors

• norepinephrine & epinephrine are roughly equivalent in activating a and b1 receptors

• sympathetic nerves secrete norepinephrine into synaptic junctions therefore concentrations of norepinephrine there is high (much higher than circulating epinephrine from adrenal medulla)

• epinephrine is much more potent in activating B2 receptors

• at low concentrations, epinephrine primarily stimulates B2-adrenoceptors (one major effect is vasodilation)

Gas-AC coupled signaling

• ephinephrine or norepinephrine binds to b adrenergic receptor and activates Gas

• AC activated to produce cAMP from ATP

• cAMP binds to inhibitory regulatory subunit of the inactive PKA leads to dissociation of regulatory subunit, which releases active enzyme (catalytic subunit of PKA)

• PKA (catalytic subunit) phosphorylates many substrates

• one important substrate: CREB = cAMP response element binding protein (transcription factor)

• CREB binds to consensus CRE in basal state, but when phosphorylated is activated to increase transcription

catecholamine signaling B1 receptors

• B1 receptors located mostly in heart kidneys and adipose tissue

• one effect of thyroid hormone signaling, increase levels of cardiac B1 receptors

• in sinoatrial and atrioventricular nodes (increase heart rate and contraction)

• in renal juxtaglomerular apparatus-stimulates renin secretion

effects of B1 receptor signaling

• increase heart contraction force and rate

• increase renin

• increase lipolysis in adipose

catecholamine signaling beta receptors overall

• beta 2 receptors

• located mainly in smooth muscles of arterioles, veins, and bronchi-mediate relaxation

• also elsewhere include in locations of beta one receptors (e.g. increase heart rate and force of contraction)

• metabolic effects due to presence in pancreas, adipose tissue, skeletal muscles, liver

beta 2 receptor effects

• increase smooth muscle relaxation and increase vasodilation (increase blood flow to cardiac muscle and skeletal muscle)

• increase skeletal muscle contraction speed

• increase bronchiolar smooth muscle relaxation & dilation/oxygen supply

• increase blood glucose due to increase glycogenolysis & increase gluconeogensis

a2-adrenergic receptors

• near (presynapses) of sympathetic nerves: negative feedback inhibition of norepinephrine release

• decrease smooth muscle relaxation and therefore increase vasoconstriction for some blood vessels (skin arterioles)

• decrease lipolysis in adipose tissue

• decrease insulin & glucagon secretion

IP3 (inositol triphosphate) & DAG (diacylglycerol)

• phsphatidylinositol (4,5)-biphosphate = a plasma membrane phospholipid that is cleaved by phospholipase C to produce IP3 and DAG

• IP3: diffuses within the cytosol; binds to IP3 receptors, which are Ca permeable channels that release Ca from endoplasmic reticulum

• DAG: remains within the membrane; recruits Ca dependent protein kinase C

a1- adrenergic receptors

• increase smooth muscle contraction

• increase vasoconstriction (increase blood pressure)

• increase contraction of radial muscle of iris (Pupil dilation)

• increase pilomotor smooth muscle contraction in skin (hairs stand up)

• increase contraction of spleen volume (expels red blood cells into circulation)

• increase blood glucose by stimulating glycogenolysis & gluconeogenesis in liver

what happens when plasma concentrations of epinephrine are high

it can stimulate a1-adrenoreceptors sufficiently to override B2-adrenoreceptor-mediated vasodilation & cause vasocontriction (where a1-adrenoceptors are expressed)

catecholamine signaling

• specific effects determined by distribution of receptor subtypes across different tissues, concentrations of respective ligands (Hormones/neurotransmitters)

• collectively lead to effects such as increased heart rate and blood pressue, increased ventilation & oxygen supply, blood flow preferentially increased towards some tissues (muscle) but not others (Constriction of vessels supplying GI tract, kidney, etc), mobilization of nutrients (glucose, free fatty acids)

• catecholamines are among the shortest lived signaling molecules in plasma, circulating half life is between 10-100s (half in circulation are bound to albumin)

• most removal due to reuptake by sympathetic nerve terminals or by enzymatic metabolism (in many tissues), then excreted in urine