Adv Pathophysiology Unit 2 Page 1 of 19 - people.musc.edupeople.musc.edu/~decristc/Adv Patho/Unit 2 nervous system/advpatho...Adv Pathophysiology Unit 2 Page 1 of 19 . File: advpatho_unit2_5recept.pdf

Adv Pathophysiology Unit 2 Page 1 of 19

File: advpatho_unit2_5recept.pdf Source: C. DeCristofaro, MD

Learning Objectives for this file: 1. Neuron receptors and neurotransmitters 2. Presynaptic & Postsynaptic neurons 3. End-organ receptors and tissue effects



PNS NEURONS, NEUROTRANSMITTERS, NEURORECEPTORS: What is covered in this file – this page summarizes it all. So, memorize it when you are done with the file!! Also, a pictorial cheat sheet just for you ! on the very last page & in a separate file for printing. NEUROTRANSMITTERS (NTs): the chemicals released by neurons to get the synapse (the gap between cells). VOLUNTARY CONTROL: • The somatic nervous system, uses ACh neurotransmitter • Is simply an outflow of a neuron from the spinal cord that ends up on the effector organ • The effector organ is always SKELETAL MUSCLE • Where the nerve meets the muscle is the NEUROMUSCULAR JUNCTION (NMJ) • The ACh receptors here are nicotinic • This is the only place we can control our bodies with conscious thought (everything else is

autonomic, not under conscious control) AUTONOMIC CONTROL: Outside of our conscious control (“automatic” = “autonomic”) • It is more complicated – the outflow from the spinal cord is the presynaptic (preganglionic)

neuron which always releases ACh • It meets up with another neuron, the postsynaptic (postganglionic) neuron • These neurons uses ACh, EP, NE, DA, NO neurotransmitters that then land on the

effector organs (cardiac muscle, smooth muscle, glands) • Sympathetic:

o The postganglionic neurons are in ganglia that are the chain ganglia (communicate with one another to send message to all parts of the body), and ganglia in other areas (e.g. splanchnic), and the adrenal medulla (a bunch of cell bodies of postganglionic neurons)

o The postganglionic neurons can travel very far, branch all over, and affect large areas of the body

o These postganglionic neurons release catecholamine NTs EP, NE, DA o Therefore, often called “adrenergic” system (catecholamine NTs) o An exception to the catecholamine release is some of these sympathetic neurons

release ACh • Parasympathetic:

o The postganglionic neurons are located very close to the effector organ o They do not branch or communicate all over (more “discrete” innervation) o These postganglionic neurons release ACh (and the exception to the rule, NO) o Therefore, often called “cholinergic” system (ACh NTs) o The ACh receptors here are muscarinic

WHAT ELSE TO KNOW? • The above information is about the chemicals released by the neurons (NTs) • THEN, in order for the NTs to work, they land on receptors that alter the cell physiology • So, you also need to learn the “second half” of the story – what receptors are on what

organ systems or tissues that react to the different NTs and what will be the result of this receptor activation



SYMPATHETIC DIVISION

Thoraco-lumbar outflow Preganglionic: Acetylcholine (ACh) Postganglionic:

• Norepinephrine (NE) • Epinephrine (EP) • Dopamine (DA) • Acetylcholine (ACh)

PARASYMPATHETIC DIVISION Cranio-Sacral outflow Preganglionic: ACh Postganglionic:

• ACh



Autonomic Nervous System (ANS): • all presynaptic

neurons are cholinergic and synapse with nicotinic receptors

• most postsynaptic neurons are adrenergic and synapse with alpha or beta receptors

• some postsynaptic neurons are cholinergic and synapse with muscarinic receptors

Neurotransmitter Pathways of the Peripheral Nervous System (PNS): made up of the somatic (voluntary, skeletal muscle) and autonomic (sympathetic & parasympathetic).

• all somatic neurons are cholinergic (synapse at the NMJ with nicotinic receptors) • most postsynaptic sympathetic neurons are adrenergic (synapse with alpha or beta

receptors) • most postsynaptic parasympathetic neurons are cholinergic (synapse with muscarinic

receptors)



PLEASE see the CHEAT SHEET on the very last page of this file. TYPES OF NEURONS & NEUROTRANSMITTERS: Cholinergic neurons (ACh): • Release acetylcholine (ACh), synthesized from acetyl-CoA in the neuron cytoplasm,

stored in vesicles at the axon terminal (synaptic knob). • Neurons that release ACh are:

o ALL somatic motor neurons at the effector site (skeletal muscle, voluntary muscular activity, at the NMJ),

o ALL pre-synaptic neurons of the ANS (BOTH parasympathetic & sympathetic), o MOST post-synaptic neurons of the parasympathetic NS, o A FEW post-synaptic (post-ganglionic) neurons of the sympathetic NS (to

cholinergic eccrine thermoregulatory sweat glands under sympathetic control). • Clinical correlate: Agonist drugs mimicking the effects of ACh are therefore

"cholinergic" agonist drugs. Adrenergic neurons (NE & EP) release catecholamines: • release catecholamines norepinephrine (NE) and/or epinephrine (EP); adrenalin was

the old term (years ago they didn't know there were two chemicals). • Neurons that release catecholamines are:

o MOST sympathetic post-ganglionic neurons release NE (or an 80/20 mix of NE/EP) at the effector site.

o Clinical correlate: adrenergic agonist drugs are "sympathomimetic" drugs (or "adrenergic" agonist drugs -- cause symptoms similar to the actions of the sympathetic NS).

Dopaminergic neurons (DA) – a type of catecholamine: • Some post-ganglionic neurons of the sympathetic NS release dopamine (dopaminergic),

really a type of catecholamine • Most clinically important dopaminergic neurons vasodilate renal blood vessels Nitric Oxide (NO) releasing neuron – NANC cells (nonadrenergic noncholinergic): • NO was formerly called EDRF, endothelial derived relaxing factor since it vasodilates

blood vessels by relaxing their smooth muscle (e.g. vasodilatation from vascular smooth muscle relaxation)

• Released by some post-synaptic parasympathetic neurons via action of enzyme nitric oxide synthase (NOS)

• Cause activaton of guanyl cyclase enzyme to make second messengers cAMP/cGMP • Clinical correlate: all nitrite drugs (e.g. nitroglycerin) actually function as NO Co-transmitters (other NTs): • Enkephalin (opioids), neuropeptide Y, GABA, serotonin (5-HT), substance P, vasoactive

intestinal peptide (VIP), gastrin-releasing peptide (GRP), cholecystokinin (CCK), calcitonin gene-related peptide (CGRP)

• Many more…we still do not know the full roles of many of these neurotransmitters



BASIC SCIENCE OF NEUROTRANSMISSION – OVERVIEW:

• chemicals used to transmit information across synapses are called neurotransmitters (NTs)

SOMATIC: • Somatic motor neuron releases ACh (cholinergic) at the effector site (the NMJ), which

has a nicotinic cholinergic receptor. • Stimulates the skeletal muscle to have an action potential, Calcium influx & then a

contraction. SYMPATHETIC: Presynaptic (Preganglionic) Neuron: • Cholinergic (releases ACh) that diffuses to the cholinoceptor (nicotinic receptor) on

the post-ganglionic neuron. Postsynaptic (Postganglionic) Neuron: • Responds to ACh (has a cholinergic nicotinic receptor), then releases its own NT • MOST postganglionic (post-synaptic) are adrenergic & release catecholamines at the

post-ganglionic synapse (at the effector site). • Catecholamines are norepinephrine (NE) & epinephrine (EP).

o Usual mix is 80% NE & 20% EP when released from peripheral postganglionic nerves

• SOME post-ganglionic (post-synaptic) neurons release Ach. o These are “exceptions” to the rule o Include cholinergic sweat glands under sympathetic control (thermoregulatory

sweat glands) & vascular smooth muscle (blood vessels) in skeletal muscle under sympathetic control

• SOME post-ganglionic (post-synaptic) neurons release dopamine • SOME post-ganglionic (post-synaptic) neurons that are also adrenergic release mostly

epinephrine – not nerve cells leading to other organs, BUT the adrenal medulla cells o The cells or the adrenal medulla area actually modified post-ganglionic

sympathetic nervous system cells o They release a different ratio of EP/NE – they release 80/20 mix of EP/NE o AND they send their NTs systemically directly into the bloodstream, thus having

effects on ALL body organs.



More on adrenergic (catecholamine) Transmission: • Synthesis of NE/EP/DA (catecholamines):

o Precursor tyrosine is transported into the cell (linked Na-transport) DOPA o Dopamine NE (then packaged into storage vesicles)

• Action of NE/EP/DA (catecholamines: o NE/EP Activate alpha or beta receptor on effector organ o DA activates dopamine receptor on effector organ

• Getting rid of catecholamines after they have done their job: o After diffusing away from the adrenoreceptor, the NE is taken back up (re-uptake)

by the neuron & supportive cells (glia) & smooth muscle cells. o Once back in the cell, the NE is metabolized by monoamine oxidase (MAO)

enzyme, and breakdown products excreted in urine as VMA (vanillyl-mandelic acid) & metanephrines.

• Clinical correlates: o Lab assessment of sympathetic activity (synthesizing catecholamines): 24-hr urine

for VMA + metanephrines (metabolic products) o Drugs blocking re-uptake include cocaine & antidepressants (allow a longer

action of NE at the receptor site) o Other drugs prevent the breakdown of catecholamines, such as antidepressant

Monoamine oxidase inhibitors (inhibit the enzyme that degrades NE)



PARASYMPATHETIC NEUROTRANSMITTERS: • ALL the pre-synaptic neurons release Ach • MOST of the post-synaptic neurons also release ACh

Presynaptic neuron: Cholinergic, releases ACh (a choline ester). Postsynaptic neuron: • Responds to ACh since it has a nicotinic cholinergic receptor • Then, the neuron releases its own NT

o MOST are cholinergic & release acetylcholine (ACh), which diffuses across the synapse to the effector cell (which has a cholinoceptor

o SOME postsynaptic parasympathetic neurons release nitric oxide (NO), mostly at blood vessels causing vasodilatation

Cholinergic neurotransmission: get rid of the NT when it has done its job? • Synthesis of ACh:

o Choline brought into the cell by a linked Na-transport o Ach = acetyl-CoA (mitochondria) + choline

• Action of ACh: o ACh diffuses across synpase to cholinoceptor on the next cell to activate the

nicotinic receptor on this cell o In the parasympathetic system, the next cell is a neuron, which in turn makes its

own NT (ACh) which activates the muscarinic receptor on the effector organ • Getting rid of ACh when it has done its job:

o ACh then diffuses off the receptor and is degraded by the enzyme acetylcholinesterase right in the synapse

o Acetylcholinesterase is located all over the body – in the tissues & the RBC. o There are related cholinesterase enzymes (ChE), that also degrade ACH, including

pseudocholinesterase. (In the CNS, there is also butylcholinesterase)



Nitric Oxide neurotransmission: • NANC cells (nonadrenergic noncholinergic) in the blood vessel release nitric oxide (NO) • Synthesis:

o L-arginine (an amino acid) is acted upon by an enzyme called nitric oxide synthase (NOS)

o Both oxygen and energy (in the form of NADPH) is required for this process • NO then binds to the cytoplasmic receptor enzyme (guanylyl cyclase) produces

cGMP as a secondary messenger • cGMP dephosphorylates myosin light chains, thus relaxing the vascular smooth muscle

cells (vasodilatation and increased blood flow) • Note that any nitrate drug turns into NO in the body and has the same effect • cGMP is degraded by specific enzymes called phosphodiesterases (PDEs) • PDEI drugs keep the cGMP around longer for increased NO effect



RECEPTORS OF THE PNS: found on neurons themselves and on effector cells REMEMBER – the answer to every question is “RECEPTORS”… Once you understand the NTs, you now have to understand the receptors… neurotransmitters meet up with a specific RECEPTOR on the TARGET CELL Peripheral ACh Receptors that are Nicotinic: • ion channel receptor affecting electrolyte flow • Found on:

o all postsynaptic neurons of the ANS o all skeletal muscle (NMJ receptor)

• Clinical correlate – pseudocholinesterase deficiency: o pseudocholinesterase deficiency is a genetic condition that results in prolonged

muscle paralysis after anesthesia, since a common anesthetic agent is succinylcholine that interacts with the nicotinic receptors to induce muscle paralysis.

o Deficiency of ChE (cholinesterase enzyme) would result in prolonged muscle paralysis.

o If this should happen to a patient, familial counseling is mandatory to prevent this from happening to other family members.

o A blood test for levels of pseudocholinesterase enzyme level is ordered • Clinical correlate – Myasthenia gravis (MG):

o Autoimmune destruction of nicotinic receptors (circulating antibody to ACh receptor)

o Fatiguability of skeletal muscle that recovers with rest o Treated with

AChEIs that inhibit degrading enzyme (acetylcholinesterase) to keep ACh around longer

Steroids to blunt the immune system Thymectomy to eliminate thymic proteins that may be triggering the

autoimmune reaction Good overview: http://www.nejm.org/doi/full/10.1056/NEJMra1602678

http://www.nejm.org/doi/full/10.1056/NEJMra1602678



Peripheral ACh Receptors that are Muscarinic: • cholinoreceptors (respond to ACh) on the effector organ cell are muscarinic (respond to

ACh & muscarine, both esters) • Found on:

o MOST effector organs of the parasympathetic NS You will often hear clinicians therefore refer to the parasympathetic

system as “muscarinic” or “cholinergic” or “vagal” (since this is the main parasympathetic nerve)

o SOME effector organs of sympathetic NS (smooth muscle blood vessels, thermoregulatory sweat glands) – these are the “exceptions” to the rule for the sympathetic NS

• SUB-types of muscarinic receptors: o Use the G-linked system of cell signaling and must therefore use secondary

messengers (DAG-IP3 & cGMP) that will affect potassium (K) flux across the membrane

o These muscarinic receptors exist as subtypes (M1, M2, M3, etc) distributed to different body tissues in different amounts

• Parasympathetic Examples: o Ciliary muscle (contracts for near accommodation) o Iris circular muscle (contracts for focus, miosis, and increased flow out of aqueous

humor in anterior chamber into canal of Schlemm) o Heart (negative inotropy & chronotropy via vagal parasympathetic action),

lung (bronchiolar constriction & a/w narrowing) o GI tract (contraction muscle walls, relaxation sphincters, increased secretions,

stimulates myenteric plexus) o GU tract (contracts bladder wall muscle, relaxes internal sphincter, contracts

pregnant uterus). • Clinical correlate:

o Some newer drugs for overactive bladder specifically block the M-subtype of receptor found on bladder tissue (M3)

o Thus less side effects due to less effects on other muscarinic receptors in other areas (such as heart & brain)



Peripheral NO receptors: • Vascular smooth muscle vasodilatation (like erectile tissue & some other visceral tissues). • The receptor here is actually an enzyme (guanyl cyclase) which is activated to produce

second messenger cAMP or cGMP



Peripheral Catecholamine Adrenoreceptors: • Respond to catecholamines NE & EP from postsynaptic sympathetic neurons • Exist as subclasses, alpha & beta • The subclasses themselves have subclasses – the clinically important ones are:

o alpha-1 (alpha-2 is less clinically important) o beta-1 o beta-2 o beta-3

• The location of the receptor determines the physiologic action that results • See BELOW for clinically relevant summary



Dopaminoreceptors: (DA receptors, DARs) • Respond to dopamine from postsynaptic sympathetic neurons • In the periphery they are mainly clinically significant due vasodilatation of renal blood

vessels • In the CNS they have multiple roles (movement, endocrine effects,

pleasure/reinforcement)



TARGET TISSUE RECEPTORS SUMMARY: Cholinoceptors: TWO TYPES (and subtypes of these) • NICOTINIC: respond BOTH to ACh & nicotine (an alkaloid). These receptors use the

ion-channel type signaling system. o REMEMBER THAT THESE RECEPTORS ARE FOUND AT THE SYNAPSE OF

THE FIRST NEURON RELAY (ANS & SOMATIC) o On the NMJ:

• the motor endplate of skeletal muscle, ACh effectd is coupled to calcium influx & skeletal muscle contraction (somatic NS)

• ACh at the NMJ voluntary control skeletal muscle contraction o On ALL Post-synaptic ANS neurons:

• ACh released by presynaptic neurons of the ANS • stimulate nicotinic receptors on the sympathetic ganglia and the adrenal

medulla, as well as parasympathetic postsynaptic neurons o these can also exist as subtypes (especially in the brain)

• MUSCARINIC: o Does not respond to nicotine, ONLY responds to ACh & muscarine (found in

mushrooms, Amanita muscaria – esters) o Found on the peripheral effector organs (innervated by most post-synaptic

parasympathetic neurons) that respond to ACh (e.g. cardiac muscle) o They are G-protein linked type receptors (use second messenger system) o They exist as subtypes – M1, M2, M3 – with distribution of these different

subtypes to different tissues. Adrenoceptors: TWO TYPES (and subtypes of these) • either ALPHA or BETA receptors, respond to the catecholamines (NE and EP) • Both alpha and beta receptors exist as subtypes – alpha-1, beta-1, beta-2, etc. • ALPHA RECEPTORS:

o The alpha-1 receptors as they are most clinically significant – on blood vessels o e.g. arteriolar muscle for peripheral vasoconstriction and other smooth muscle

(e.g. prostatic urethra, pupillary mydriasis) • BETA RECEPTORS:

o Beta-1 receptors in heart (increased inotropy & chronotropy) & renin release from kidney

o Beta-2 receptors cause relaxation (lung – bronchial relaxation) o Beta-3 receptors cause metabolic effects (lipolysis) — found on adipocytes; also

cause relaxation of the smooth muscle of the urinary bladder Dopaminoceptors: respond to dopamine neurotransmitter. NO receptors:

• Clinically important target tissue is mostly the vascular smooth muscle vasodilatation



Look at the cheat sheet on the very last page… MY "REMEMBER" PEARL: the neuron relay race, handing off the impulse to one another by releasing neurotransmitters that land on receptors. FIRST RELAY NEURON: releases ACh & abuts nicotinic receptors (alkaloid) Somatic: CNS PNS (ACh) Effector Organ (Skeletal Muscle, NMJ — NICOTINIC receptor) Parasympathetic: CNS presynaptic neuron (ACh) (maybe) local ganglion neuron (NICOTINIC receptor) Sympathetic: CNS preganglionic neuron (ACh) sympathetic ganglion neuron (NICOTINIC receptor) SECOND RELAY NEURON: varies depending on which division of the ANS Parasympathetic: Chemical ligand: ACh & exception (NO) Target tissue receptors: muscarinic receptors (esters) postsynaptic neuron (uses ACh) effector organ (muscarinic receptor) postsynaptic neuron (uses NO) effector organ (NO receptor on vascular smooth muscle of some visceral tissues for vasodilatation) Sympathetic: Chemical ligands are: NE or EP & exceptions (dopamine, ACh)

Target tissue receptors: alpha, beta, dopamine, muscarinic receptors postganglionic neuron (EP, NE) effector organ (alpha-1, beta-1, beta-2, beta-3) postganglionic neuron (dopamine) effector organ (dopaminoceptor) postganglionic neuron ( ACh) effector organ (cholinoreceptor, muscarinic) (thermoregulatory sweat glands, vascular smooth muscle of skeletal muscle bld vessels) The chart below is basic and leaves out the “exceptions” to the rule.



CLINICAL CORRELATE – SCORPION ENVENOMATION From: Isbister, G.K. & Bawaskar, H.S. (2014) Scorpion envenomation. New England Journal of Medicine, 371, 5, pp. 457-463. Retrieved from: http://www.nejm.org/doi/pdf/10.1056/NEJMra1401108 (Used with permission from personal subscription)

http://www.nejm.org/doi/pdf/10.1056/NEJMra1401108



SUMMARY PERIPHERAL NEUROTRANSMITTERS & RECEPTORS: CATECHOLAMINES: NE & EP released by most postsynaptic sympathetic neurons. RECEPTORS: adrenoreceptors of different subclasses of alpha & beta. • alpha-1: vascular smooth muscle (vasoconstriction), pupillary radial dilator muscle

(contraction dilates pupil mydriasis), pilomotor smooth muscle (erector pili – goosebumps), GI tract (sphincter contraction, liver glycogenolysis & gluconeogenesis, inhibition of myenteric plexus & relaxation of walls), GU tract (pregnant uterus contraction, ejaculation & detumescence of sexual organs – orgasm, bladder sphincter contraction), skin (stimulates apocrine sweat glands -- stress sweating, not thermoregulatory)

• alpha-2: platelets (aggregation), kidney (inhibits renin release, promotes renal blood vessel dilatation), inflow of aqueous humor.

• beta-1: heart (positive inotropy & chronotropy), kidney (renin release) • beta-2: skeletal muscle (stimulates potassium uptake during exercise), liver

(glycogenolysis & gluconeogenesis), smooth muscle (lung bronchioles & blood vessels relaxation & dilatation), GU tract (pregnant uterus relaxation, bladder wall relaxation), GI (relaxation of muscle walls), muscle (glycolysis). Lots of catecholamines may cause metabolic acidosis (lactic acidosis) due to combination of the above effects.

• beta-3: fat cells (activates lipolysis); smooth muscle of urinary bladder (relaxation) DOPAMINE (DA): some postsynaptic sympathetic neurons. RECEPTORS: dopaminoceptors (DARs) dilate renal blood vessels ACETYLCHOLINE (ACh): released by all presynaptic autonomic neurons (sympathetic & parasympathetic neurons), some postsynaptic sympathetic, most postsynaptic parasympathetic, and all somatic (NMJ). RECEPTORS: nicotinic AChR & muscarinic AChR • nicotonic (use ACh): all presynaptic autonomic & the NMJ (most clinically important) • muscarinic (use ACh):

o Sympathetic ("exceptions"): thermoregulatory sweat glands (increased activity of cholinergic eccrine sweat glands) & skeletal muscle blood vessels.

o Parasympathetic (most): postganglionic. NITRIC OXIDE (NO): some postsynaptic parasympathetic. RECEPTORS: vasodilates blood vessels by relaxing vascular smooth muscle


Source: C. DeCristofaro, MD

Voluntary (SKELETAL) Muscle Activity Cholinergic Presynaptic Neuron Cholinergic Skeletal Muscle (Neuromuscular Junction, NMJ) ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ MOSTLY Cholinergic Presynaptic Adrenergic Postsynaptic Neuron: EP20%, NE 80% EXCEPTIONS: OR Adrenal Medulla (EP 80%, NE 20% to bloodstream) Cholinergic Presynaptic Neuron Cholinergic Postsynaptic Cholinergic Presynaptic Neuron Dopaminergic Postsynaptic ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- MOSTLY Cholinergic Presynaptic Neuron Cholinergic Postsynaptic Neuron EXCEPTION:

Cholinergic Presynaptic Neuron NANC Postsynaptic Neuron

CHEAT SHEET: PERIPHERAL NERVOUS SYSTEM = THE SOMATIC (VOLUNTARY, SKELETAL MUSCLE) AND THE AUTONOMIC (INVOLUNATARY -- SYMPATHETIC & PARASYMPATHETIC)

SOMATIC ACh Nicotinic

Receptor

SYMPATHETIC ACh

End Organ: Beta-1 (heart/kidney) Beta-2 (lung) Beta-3 (metabolic, bladder relax) Alpha-1 (GU, blood vessels)

ACh

Nicotinic Receptor

Nicotinic Receptor

End Organ: Thermoregulatory Sweat glands & skeletal Muscle blood supply

PARASYMPATHETIC

ACh

Nicotinic Receptor

End Organ: Glands, heart , GI (gut) GU smooth muscle Vascular smooth

muscle

ACh

Nicotinic Receptor

End Organ: Vascular smooth muscle vasodilatation

Alpha or Beta Receptor

Muscarinic Receptor

Muscarinic Receptor

Nitric Oxide Receptor cGMP

ACh Nicotinic Receptor

Dopamine Receptor

End Organ: Cardiovascular Renal blood flow

ACh

NO

Dopamine

EP NE

ACh

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Adv Pathophysiology Unit 2 Page 1 of 19 - people.musc.edupeople.musc.edu/~decristc/Adv Patho/Unit 2 nervous system/advpatho...Adv Pathophysiology Unit 2 Page 1 of 19 . File: advpatho_unit2_5recept.pdf