PGY452 552 Human Physiology Endocrinology 12 Epinephrine the fast stress response A B C D The adrenal medulla Synthesis of epinephrine Control The diversity of adrenergic receptors Epinephrine is a catecholamine HN CH3 Circulation CH2 HO CH Amide hormone Adrenal medulla OH OH Chromaffin granule cells Not a true gland Specialized sympathetic ganglion C Medulla Sympathetic synapses Blood supply From cortex Allows cortisol regulation granules 2 Epinephrine works with the Adrenal sympathetic nervous system medulla extension of the autonomic nervous system FAST endocrine Neurogenic Connects endocrine SNS stress response Stress Norepinephrine released across synapses bloodstream Adrenal medulla Neurohormones Usually affect the same Chromaffin cell tissue Effects difficult to Epinephrine separate Acetylcholine Preganglionic Epinephrine sympathetic nerve norepinephrine Spinal cord catecholamines Post ganglionic Systemic sympathetic neuron Norepinephrine 3 Epinephrine is made from tyrosine in chromaffin cells Epinephrine in granule is 0 5 M Synthesized stepwise from tyrosine Stored in chromaffin granules Complexed w a protein ATP Granule HN H CH2 H Chromogranin Concentrates hormone CH3 HO CH OH OH NH2 HOOC CH CH2 Tyrosine hydroxylase HOOC NH2 Amino acid decarboxylase NH2 CH H CH2 Norepinephrine NH2 CH CH2 CH2 HO CH DA OH OH OH OH OH Tyrosine DOPA Dopamine Phenyl ethanolamine Nmethyltransferase OH Epinephrine NE Dopamine OH H hydroxylase 4 Epinephrine synthesis regulated by CRH ACTH Cortisol axis Note that epinephrine is not directly involved in HPA feedback Stress CRH Stress Release signal Cortisol ACh ACTH ACTH tyrosine ACTH 5 Regulation integrated at cellular level 2 plasmin s AC Na ACh 4 AChR Ca2 1 cAMP cAMP Ca2 Cortisol ACTH ACh release 3 Na PKAii cAMP cAMP PKA PKAii cAMP NE DA Dopamine A PK PKA P ol is rt co DA hydroxylase NE Phenyl ethanolamineN methyltransferase Tyrosine DOPA Tyr hydroxylase 6 Regulation integrated at the cellular level Levels of control 1 ACTH activates PKA which up regulates transcription of epinephrine synthetic enzymes tyrosine hydroxylase and dopamine hydroxylase as always it is enough to know ACTH PKA epinephrine synthetic enzymes 2 Cortisol up regulates transcription of a different epinephrine synthetic enzyme Phenyl ethanolamine N methyltransferase PNMT The overall effect is to increase the amount of epinephrine made and stored in the granules complexed to chromogranin This allows more epinephrine to be released in a pulse and for pulses to occur more frequently that is the strength and frequency of the fast stress response 3 To release epinephrine Acetyl Choline ACh binds to the ACh receptor which is a ligandgated ion channel It allows sodium to enter the cell causing membrane depolarization That change in membrane potential activates a voltage gated calcium channel which allows calcium into the cell stimulating epinephrine chromogranin release just like a peptide hormone 4 Chromogranin is digested by the protease plasmin the proteolytic digestion products of plasmin FYI called catestatin inhibit the AChR blocking further release of epinephrine for a short time Epinephrine clearance steroid like t 1 minute Metabolized by Vascular endothelium Heart Kidney Amino acid transporters Liver MHPG Catacholamine O methyltranserase COMT Monoamine oxidase COMT Vanillylmandelic acid HN CH3 CH2 HO CH O Excreted as VMA CH HO MAO CH2 OCH3 CH OH Excreted HO CH O CH OCH3 HO OH HN CH3 COMT OH CH OH MAO COMT OH OH 8 Signaling catecholamines bind to nine G protein coupled receptors Adrenergic receptors a2 A B C b1 b2 b3Gas s Defined pharmacologically Multiple subtypes of each Vary in tissue distribution Key to effects Gai AC i Gaq a1 A B D q PLC cAMP PKA Affinity NE E E NE Does not predict effects PKC 9 Major effects involve fight or flight Pain BLOOD FLOW IS KEY 1 2 Brain Glucagon Insulin Pancreas GNG 2 Liver Lipolysis Cardiac output Heart 3 Adipose Smooth muscle relaxation Blood flow Smooth muscle contraction Blood flow Muscle 1 Lungs Spleen GI Bladder Reproductive organs 10 Epinephrine mobilizes glucose Amino Acids Brain NEFA TA G Glycogen 2 4 4 Adipose o xid atio n Glycogen 4 Liver ATP oxphos 4 Citric acid cycle a2 Insulin Pyruvate I ATP Muscle HSL Ketones Glc Pancreas glucagon 11 Glycogen metabolism differentiates cortisol from epinephrine Cortisol promotes glycogen synthesis to ensure long term supply of glucose to the CNS Cortisol Glycogen Epinephrine promotes glycogen breakdown to ensure short term supply of glucose to the CNS Epinephrine Liver 12 Catecholamines cortisol work together Fast SNS release of ACh from sympathetic ganglia Epinephrine from adrenal medulla Norepinephrine from SNS Mobilize nutrients O2 to high priority tissues Fast glucose mobilization Short t Little regulation HPA adrenal cortex Synthesis of cortisol Activities stress adaptation Activities short term Slow Restore homeostasis Immune suppression Long term glucose mobilization CNS effects well being Fast response epi synthesis Long t Extensive regulation Two responses that proceed at different rates 13 Hormones Hormone Source Epinephrine Adrenal Medulla SNS postNorepinephrine ganglionic neurons ACTH Anterior pituitary Cortisol Adrenal cortex Type t Rcpt Stimulus Inhibition Sympathetic ACh ACTH N A Cortisol Major Effects Vascular Amide 1 All G Fight flight Mobilize glucose Vascular Sympathetic ACh Amide 1 All G N A Fight flight ACTH Mobilize glucose cortisol Peptide 10 G s CRH Cortisol synthesis adrenal cortex Inflamation Steroid Long Nuclear ACTH mobilize glucose Other liver glycogen epinephrine aldosterone liver glycogen Although I really didn t devote much time to norepinephrine you should have some ideas of it s properties It does have effects distinct from epinephrine but those effects are outside the scope of the course 14 Notes SLIDE 4 As always don t memorize the synthesis pathway just the stuff in the bullet points SLIDE 8 This is actually an amazingly complex interesting topic and I have left a lot out o What I m interested in you knowing is Epinephrine is metabolized more or less like a steroid by sequential chemical modification to inactivate followed by excretion of the metabolites The reason that it has such a short half life is that it can enter cells through amino acid transporters and chemically inactivated in their primary targets the vascular wall o Also MHPG stands for 3 methyl 4 hydroxyl phenylglycol Metabolism of norepinephrine is somewhat like epinephrine with some