Slide 1Epinephrine is a catecholamineEpinephrine works with the sympathetic nervous systemEpinephrine is made from tyrosine in chromaffin cellsEpinephrine synthesis regulated by CRH-ACTH-Cortisol axisRegulation integrated at cellular levelRegulation integrated at the cellular levelEpinephrine clearance: steroid-likeSlide 9Major effects involve fight or flightEpinephrine mobilizes glucoseGlycogen metabolism differentiates cortisol from epinephrineCatecholamines & cortisol work togetherHormonesNotesReview questionsPGY452/552: Human Physiology: Endocrinology12. Epinephrine & the fast stress responseA. The adrenal medullaB. Synthesis of epinephrineC. ControlD. The diversity of adrenergic receptorsAmide hormoneAdrenal medullaChromaffin granule cellsNot a “true gland”Specialized sympathetic ganglionBlood supplyFrom cortexAllows cortisol regulation2Epinephrine is a catecholaminegranulesMedullaCirculationCirculationOHCHCH2HNOHHOCH3SympatheticsynapsesC3Epinephrine works with the sympathetic nervous systemAdrenal medulla extension of the autonomic nervous systemConnects endocrine & SNSNorepinephrine released across synapses & bloodstreamNeurohormonesUsually affect the same tissueEffects difficult to separateEpinephrine + norepinephrine = catecholaminesStressStressSystemicSystemicNeurogenicNeurogenicPreganglionic sympathetic nerveSpinal cordAdrenal medullaAcetylcholineChromaffin cellNorepinephrineNorepinephrinePost-ganglionic sympathetic neuronEpinephrineEpinephrineFAST endocrine stress responseFAST endocrine stress responseSynthesized stepwise from tyrosineStored in chromaffin granulesComplexed w/ a protein:Chromogranin Concentrates hormone4Epinephrine is made from tyrosine in chromaffin cellsOHCH2CHNH2HOOCTyrosineOHCH2CHNH2HOHDopamineEpinephrineOHCH2CHNH2HOOCOHDOPATyrosine hydroxylaseDopamine β-hydroxylaseAmino acid decarboxylasePhenyl ethanolamine-N-methyltransferaseOHCHCH2NH2OHHONorepinephrine[Epinephrine] in granule is >0.5 M![Epinephrine] in granule is >0.5 M!GranuleH+H+ATPATPH+OHCHCH2HNOHHOCH3?NEDACRHEpinephrine synthesis regulated by CRH-ACTH-Cortisol axis5AChCortisolACTHACTHACTHNote that epinephrine is not directly involved in HPA feedback!Note that epinephrine is not directly involved in HPA feedback!tyrosinetyrosineStressStressRelease signalRelease signalStressStressRegulation integrated at cellular level6Ca2+Na+AChRCa2+DopamineDOPATyrosine11223344AChNa+ΔΨACh releaseACh releasePKAcortisolPKAACβγαsACTHPKAPKADANENECortisolPKAiPKAicAMPcAMPcAMPPKAiPKAicAMPcAMPPP"plasminTyr hydroxylaseDA β-hydroxylasePhenyl ethanolamine-N-methyltransferaseRegulation integrated at the cellular levelLevels of control1. ACTH activates PKA, which up regulates transcription of epinephrine synthetic enzymes tyrosine hydroxylase and dopamine β 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 ligand-gated 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.t½ <1 minuteMetabolized byCatacholamine-O-methyltranseraseVascular endothelium HeartKidneyLiverMonoamine oxidaseCOMTExcreted as VMA8Epinephrine clearance: steroid-likeOHCHCH2HNOHHOCH3Vanillylmandelic acidOHCHCH2HNOCH3HOCH3OHCHCHOCH3HOOCOMTCOMTMAOMAOOHCHCHOHHOOMAOMAOCOMTCOMTExcretedExcretedCOMTCOMTMHPGAmino acid transportersSignaling: catecholamines bind to nine G-protein coupled receptors9βγαqb1, b2, b3Defined pharmacologicallyMultiple subtypes of eachVary in tissue distributionKey to effectsAdrenergic receptorsACPLCa1 (A, B, D)a2 (A, B, C)PKCPKAPKAβγαsαi βγcAMPAffinityα: NE>E β: E>NEDoes not predict effectsGasGaiGaq10AdiposeLipolysisβ3α2Brain Pain GlucagonInsulinβ1Heartβ2 Smooth muscle r e l a x a t i o nBlood flow Blood flow LungsMuscleα1 Smooth muscle contraction Blood flow  Blood flow Liver GNGBladderGISpleen Cardiac outputReproductive organsPancreasBLOOD FLOW IS KEYBLOOD FLOW IS KEYMajor effects involve fight or flightEpinephrine mobilizes glucosePancreasglucagonInsulinGlcAdiposeHSLIMuscleATPATPBrainβ2a2oxphosATPATPCitric acid cycleLiver1144GlycogenKetonesAmino AcidsPyruvateGlycogenNEFANEFATAGTAG44β oxidationGlycogen metabolism differentiates cortisol from epinephrine12LiverCortisolEpinephrineCortisol promotes glycogen synthesis to ensure long-term supply of glucose to the CNSCortisol promotes glycogen synthesis to ensure long-term supply of glucose to the CNSEpinephrine promotes glycogen breakdown to ensure short-term supply of glucose to the CNSEpinephrine promotes glycogen breakdown to ensure short-term supply of glucose to the CNSGlycogenCatecholamines & cortisol work togetherFastSNS release of ACh from sympathetic gangliaEpinephrine from adrenal medullaNorepinephrine from SNSActivities: short-termMobilize nutrients & O2 to high priority tissuesFast glucose mobilizationShort t½Little regulation SlowHPA → adrenal cortexSynthesis of cortisolActivities → stress adaptationRestore homeostasisImmune suppressionLong term glucose mobilizationCNS effects – well being Fast response – epi synthesisLong t½Extensive regulation13Two responses that proceed at different ratesTwo responses that proceed at different ratesHormones14Hormone Source Type t(½) Rcpt Stimulus Inhibi-tionMajor Effects OtherEpinephrineAdrenal MedullaAmide <1’ All GSympathetic (ACh)ACTHCortisolN/AVascularFight/flightMobilize glucose↓ liver glycogenNorepinephrineSNS post-ganglionic neuronsAmide <1’