Chapter 3 catecholamines

Catecholamines

• Amino Acid Derived hormone type

• • Have a catechol group and an amine group • Derived from tyrosine

• • Dopamine, Norepinephrine, Epinephrine

• • Synthesized in the Adrenal Medulla

• • Primary function for NE and E • Responds to stress

Stimuli for catecholamine release

• Stress Response is the stimuli

• • Emotional Stress

  • • Fear/Anxiety • Excitement

• Physical Stress

  • • Exercise, Pain/Injury • Hypotension/Hypovolemia

• • Environmental Stress

  • • Cold/Heat • Hypoxia

• • Metabolic Stress

  • • Hypoglycemia

• Need gluocse in the blood in stressful situations through catecholamine release

Autonomic Nervous System

• • Efferent Division of Nervous System

• • Not under Voluntary Control

• • Sympathetic Branch

  • • Fight or Flight • Thoracolumbar neurons(middle of spinal cord)

• Parasympathetic Branch

  • • Rest & Digest • Cervical and Sacral neurons(start and end of spinal cord

Ganglionic Pathways

• ANS uses a two-neuron pathway

• Preganglionic Neuron & Postganglionic Neuron

• Divergence

  • • One preganglionic neuron may synapse onto as many as 32 postganglionic neurons

• SNS

  • • Short preganglionic, long post ganglionic

• PNS

  • • Long preganglionic, short post ganglionic

Receptors & Neurotransmitters in the CNS for nervous sytems

• • Preganglionic onto Postganglionic

  • • Same for SNS & PNS • ACh onto a nicotinic receptor

• Postganglionic onto Target

  • • SNS • Norepinephrine onto Adrenergic Receptor • α and β Adrenergic Receptors

  • • PNS • ACh onto Muscarinic receptor

• Sympathetic pathways use acetylcholine and norepinephrine, parasympathetic pathways use acetylcholine only

Adrenal medulla

• • Modified Sympathetic Ganglion

• SNS preganglionic neurons synapse onto this adrenal structure

• • Stimulated in response to a significant stressor

• Releases Epinephrine (80%) and NE (20%) into the blood •

  • Neurohormone • Systemic, less selective responses (any tissue with adrenergic receptors)

  • Neurons have lots of norepinephrine, but the blood requires a lot of epinephrine for stress response

Synaptic ACh Storage and Transport

• ACh is synthesized in cytosol (in the nerve terminal) and stored in vesicles

  • Golgi apparatus and ER are necessary to produce the complex vesicles

• • Vesicles (empty) are formed in the cell body
  • Transported to nerve terminal along microtubules via the motor protein Kinesin(Kinesin walk along the microtubules)

What is the enzyme responsible for ACh formation?

• • Choline Acetyltransferase

  • • Located in cytosol of axon terminal

  • • Converts Choline + Acetyl CoA to Acetylcholine

  • • Choline brought in via membrane transportetransport

Synaptic ACh Entryways

• • Vesicles contain two membrane proteins that allow entry of ACh

  • • H+ ATPase • Causes H+ to build up in the Vesicle to transport ACh as well( 1 degree = co-transporter)

  • • VAChT (Vesicle ACh Transporter) • Swaps H+ for AC(2 degree = antiporter)

ACh Release

• Vesicles with ACh dock at the membrane, but do not release ACh. • SNARE binding vesicle/membrane

• Calcium (from VG Calcium channels) binds to synaptotagmin.

• Calcium binding to synaptotagmin causes displacement of complexin

• This causes vesicle/membrane fusion and the release of vesicular contents (ACh)

• Afterwards, vesicles are reabsorbed and recycled or degraded.
  

ACH binding and Recycling

• ACh binds to target, opening sodium channels

• Sodium influx opens Voltage-Dependent Calcium Channels (VDCC)

  • • Calcium influx into the chromaffin cell or nerve terminal of SNE postganglionic neuron

• ACh in the synaptic cleft is hydrolyzed by Acetylcholinesterase to Choline and acetate

• Choline is then brought back into the preganglionic neuron via a sodium cotransporter (using sodium gradient for energy)

• acetate leaves the cell and gets metabolized by liver for excretion(no recycling)the

Norepinephrine in SNS Neurons(Tyrosine pathway)

• • Tyrosine is brought in via an AA transporter

• • Tyrosine->DOPA->Dopamine

• • Dopamine enters a vesicle and is converted to NE and stored

• • Enters via VMAT2 transport protein

• • Action Potential opens VDCC in the postganglionic neuron • Calcium influx causes vesicle release of NE.

Norepephrine in SNS Neurons

• NE activates adrenergic receptors (GPCRs) • α1, α2, β1, β2, β3

• NE is recycled via the NE transporter (NETr)

• NE induces negative feedback via α2 activation

• Some NE diffuses to blood (metabolized by the liver)

• ACH broken down by enzyme in membrane, NE is recycled by being received by a transporter and then being transported into the cell for recycling

Neuroendocrine Catecholamine Release diagram

• chromaffin cells produce catecholamine when they are activated by Ach

Adrenal Gland

• • Superior to the kidneys

• • Multilayered

  • • Different layers produce different hormones

  • • Cortex (True Endocrine Gland)

    • • Zona Glomerulosa(upper layer) • Zona fasciculata(middle thick layer) • Zona Reticularis(bottom layer)

• • Medulla (Modified Sympathetic Ganglion)

  • • Chromaffin cells • Synthesize and secrete catecholamines

Epinepherine Synthesis

The synthesis for this catecholamine hormone uses VMAT transporters (catecholamine/H+ antiporter)

• NE leaves the vesicle • Converted to epinepherine in the cytosol (via PMNT)

• Epinepherine enters vesicle

• Stored in a complex with chromogranin proteins.
  

Catecholamine Release in Chromaffin Cells

• SNS stimulation of chromaffin cells causes Na+ influx • ACh binding to nAChR

• Na+ induced depolarization opens VDCC(voltage gated ion channel) • Initiates exocytosis

• Similar to exocytosis of ACh from neurons

  • • Larger vesicles in chromaffin cells • Slower • Additional accessory proteins. • Stimulated by Calcium Calmodulin • Stimulates accessory proteins • Interacts with Synaptotagmin

• Negative Feedback •

  • Catecholamines on α2 receptors • Reduces SNARE interaction, slowing exocytosis

  • • ATP (released from vesicles) • Closes VDCC by GPCR cascade

• binds with CaM

  • • Facilitates exocytosis • Stimulates CaMK • Phosphorylates (activates) Tyrosine Hydroxylase • Leads to increased catecholamine synthesis

Effects of Cortisol

• • Stress response causes cortisol to be released from the Zona fasciculata(middle layer of the adrenal cortex)

• • Cortisol reaches the adrenal medulla

• • Venous drainage

• • Binds to nuclear receptors in chromaffin cells • Increases gene expression to induce synthesis of PNMT and VMAT( enzyme converter of norepinephrine to epinephrine and transporter of epinephrine respectively)

PACAP

• Splanchnic Nerve also secretes Pituitary Adenylate Cyclase Activating Polypeptide (PACAP)

• Binds to the PAC1R

  • • GPCR (Gs) • Leads to an increase in cAMP

  • • cAMP activates PKA • Phosphorylates and stimulates Tyrosine Hydroxylase • cAMP activates CREB (cAMP Response Element Binding Protein)

  • • Increases gene expression to induce synthesis of Tyrosine Hydroxylas

Catecholamine degredation

• enzymes present in the liver are responsible for this catecholamine process

  • Catechol-O-methyltransferase (COMT): COMT makes dihydroxy mandelic acid into vanillylmandelic acid, norepinephrine to normetanephrine, and epinephrine to metanephrine.

  • Monoamine Oxidase (MOA): MOA takes catecholamines(Norepi and epi) and converts them to dihydroxy mandelic acid

Adrenergic receptor

• GPCRs

• α1, α2, β1, β2, β3

• Activated by NE released from SNS postganglionic neurons (Neurotransmitter)

• Activated by circulated NE and Epi released from the adrenal medulla (Neurohormone)

• varying locations, sensitivities, and effects

• Beta 2 Favours epinephrine response due to the shape of the receptor.

• All beta receptors and alpha 1 are Gs(adenylate cyclase activator) A2 is GI(inhibitors adenylate cyclase AC)

CREB(cAMP Response Element Binding Protein)

• This protein is used to gain gene expression from GPCR

• More of this protean means more stimulation on GPCR to release

• • Enables gene transcription from a membrane-bound receptor

• PKA activation can activate this protein (phosphorylates CREB at Serine 133)

• • Chronic activation can lead to appreciable gene transcription(continuous activation)

  • Increased mitochondrial biogenesis • Cardiac muscle remodeling(more cardiac strength) • Uncoupling protein (UCP1) generation in brown adipose tissue receptor

Tyrosine hydroxylase

• This enzyme is made in the process of norepinephrine creation

• This enzyme is the tyrosine enzyme that makes Tyrosine to L-Dopa

• More tyrosine hydroxylase means more L-Dopa for catecholamine production

α1 Adrenergic Receptors

• Vasculature • Vasoconstriction

• Eye • Dilator muscle contraction (pupil dilation)

• GI tract • Sphincter Contraction

• Genitourinary tract • Internal urinary sphincter contraction • Vas deferens and prostate smooth muscle (mediates ejaculation).

  • closes the urinary sphincter, stops the need to go to the bathroom, and also closes smooth muscles to stop the reproduction process

  • parasympathetic nervous system is responsible for arousal; a quick sympathetic nervous system response mediates arousal

• Salivary Glands • Reduces saliva production

• Liver • Promotes glycogenolysis and gluconeogenesis • Inhibits glycogen synthesis

  • Glycogenolysis: glycogen > glucose, gluconeogenesis: glucose from carbohydrates(want more glucose during stress)

• • Pancreas • Inhibit insulin secretion

α2 Adrenergic Receptors

• Skin and Gut Blood Vessels • Vasoconstriction(want extra vasoconstriction in skin and gut, that’s why alpha has this effect)

• Sympathetic Neurons and Adrenal Medulla • Negative Feedback

• Pancreas • Inhibit Insulin Secretion • Stimulate Glucagon Secretion(glucagon encourages more glucose in blood)

• GI Tract Neurons • Reduce GI motility

• Platelets • Blood Clotting

• a constrictor 2 the death

β1 Adrenergic Receptors

• Heart • Increase Heart Rate • Increase Contractility(most important regulated area)

• Kidneys • Stimulate production of hormones (RAAS Pathway hormones) • Increase blood pressure • Decrease urine production • Increase vasoconstriction(just know RAAS pathway increases blood pressure, no need to know all hormones)

• Adipose • Stimulate lipolysis

• You only have on heart, even if you have multiple kidneys and fat

β2 Adrenergic Receptors

• Bronchial Smooth Muscle • Bronchodilation (reduces airway resistance)

• • Some Blood Vessels • Vasodilation • Muscle, coronary arteries

• • Skeletal Muscle • Stimulate glycogenolysis and lipolysis

• • Liver • Stimulate glycogenolysis and gluconeogenesis and lipolysis

• • Uterus • Uterine Relaxation

• • GI Tract Smooth Muscle • Reduced motility

• • Adipose Tissue • Stimulates Lipolysis • Pancreas • Stimulate Glucagon Secretion

• Beta 2 is for scary responses, alpha receptors and Beta1 receptors are for slight changes but crank up with large stress response.significant

• Regulated by hormones rather than neurons, slower

• Epi-pen: helps with vasodilation when there is constriction due to an asthma attack

  • epinephrine primarily affects the heart rate and airway dilation, while norepinephrine primarily functions to constrict blood vessels, thereby increasing blood pressure

• B2: 2 be slow, 2 be breathing

β3 Adrenergic Receptors

• Adipose Tissue

• • Predominantly Brown Adipose Tissue(Heat generator)
  • Some in White Adipose Tissue(main adipose storage tissue)

• • Stimulates lipolysis • Activates thermogenesis (reduced efficiency of mitochondria)

• 3 = fatty

Gs and Gi GPCRs

• β Receptors are Gs

• α2 Receptors are Gi

  • • Result in activation or inhibition of Adenylate Cyclase (AC)(GS activate, GI inhibit)

• AC(Adenylyl cyclase) generates cAMP • cAMP stimulates PKA (binding to regulatory proteins) • PKA phosphorylates various enzymes in the cell to activate them

AKAP and Mitochondria

• • PKA Regulatory proteins can bind to AKAP (a kinase anchoring protein)

  • • AKAP and Phosphodiesterase (PDE) tether PKA to the mitochondrial membrane.

  • • cAMP then binds to PKA at the mitochondrion and is removed by PDE

• • This enhances PKA function at the mitochondrion

  • • Phosphorylates StAR • Increases metabolite transport across the mitochondrial membrane

  • • Phosphorylates Cytochrome Oxidase • Increases mitochondrial efficiency and enhances Cytochrome Oxidase Activity

• • β adrenergic receptor activation acutely improves mitochondrial function

Gq GPCRs

• α1 receptors

• • Receptor activation leads to activation of Phospholipase C

• Converts PIP2 to IP3 and DAG

• • DAG activates PKC and IP3 induces calcium release from the SR

Function 1 of catecholamine: Maintain Blood Glucose

• Liver increases glycogenolysis and gluconeogenesis

• • Liver decreases glycogen synthesis

• • Increases hepatic glucose production helps to keep blood glucose from dropping.

• • SM(skeletal muscle) increases glycogenolysis (alternative to blood glucose)

Function 2: Increase availability of other fuel sources

• • SM glycogenolysis • (use glycogen instead of glucose)

• • SM increases lipolysis • (use fatty acids instead of glucose)

• • AT increases lipolysis • (use fatty acids instead of glucose) • Increase blood fatty acid concentration for use by other tissues (including liver and SM)

• • Liver Increases lipolysis • Increases fatty acid oxidation in the liver for ATP, instead of glucose

• • Liver increases ketogenesis • Increased blood fatty acid concentration (from AT lipolysis) stimulates ketogenesis in the liver • Increased fatty acid oxidation in the liver stimulates ketogenesis in the liver

Function 3: Alter secretion of other hormones to aid with functions 1 & 2.

• • Increased glucagon from pancreas • Increase hepatic glucose production (via glycogenolysis and gluconeogenesis)

• • Decreased insulin secretion • Decrease blood glucose utilization by non-brain organs.

Stimulation of Lipolysis in Adipose Pathway

• Epinephrine increase PKA. PKA phosphorylates PLIN1 to dissociate from CGI-58 and attach to HSL, replacing GOS2 stopping inhibition and activating ATGL and HSL to cause lipolysis in adipose tissue

Stimulation of Lipolysis in Muscle(enzymes used)

• PKA phosphorylates PLIN5 AND CGI-58 as well as HSL in order to cause lipolysis in this tissue type(HSL also stimulated in adipose),