PHA 334 - ANS (Lecture #3) AFTER QUIZ #1 (old)

Acetylcholine (ACh) and Norepinephrine (NE) are the major neurotransmitters of the ANS that drive its effects on organs. The effects are mediated by what?

the receptors on SCAG that ACh and NE bind and activate

ACh is released by cholinergic nerve fibers at:

Both PNS and SNS preganglionic axons and All PNS postganglionic axons

NE is released by adrenergic nerve fibers at:

All SNS postganglionic axons, except those at sweat glands, which release ACh

Parasympathetic—________ nerve fibers innervate organs/tissue

cholinergic

Sympathetic— nerve fibers innervate organs/tissue

adrenergic nerve fibers, except at sweat glands – cholinergic

SNS also uses ________ as a blood hormone released from the adrenal medulla

epinephrine

Acetylcholine is synthesized from what?

choline

Acetylcholine is stored where?

in vesicles in the presynaptic terminal

Acetylcholine is removed from the synaptic cleft by what?

Acetylcholinesterase (AChE)

Acetylcholine is described as:

shorter lived and dissipates faster

Norepinephrine is synthesized from what?

tyrosine

Norepinephrine is removed from the synaptic cleft by what?

mostly via the Norepinephrine Transporter

Norepinephrine is described as:

slower, but longer lasting effects

Neurotransmitter effects are terminated by:

reuptake through transport proteins, enzymatic degradation, or diffusion away from the synapse

ACh message terminated by:

acetylcholinesterase (AChE)

NE message is terminated mostly by:

reuptake through the norepinephrine transporter (NET)

ACh vs NE duration:

ACh = faster release, response lasts shorter NE = slower release, response lasts longer

PNS stimulation elicits short-lived and highly localized control over effectors because:

ACh is quickly destroyed by acetylcholinesterase* Nerves have few branches – 1:4 Postganglionic fibers are often inside the target tissue

SNS tends to be longer-lasting with body-wide effects because:

NE is inactivated more slowly than Ach Nerves have many branch points/high divergence – 1:20 NE and EPI hormones from adrenal medulla have prolonged effects

ANS neurotransmitters act at 2 groups of receptors:

Ligand-gated ion channels and G protein-coupled receptors (GPCRs)

Ligand-gated ion channels:

Neurotransmitter binds and opens the channel, allowing select ions to flow in/out Rapid responses Cholinergic and on ganglia

G protein-coupled receptors (GPCRs):

Neurotransmitter binds, which increases the affinity of the receptor for an intracellular G protein complex; this activates the G protein, which activates its effector(s), typically enzymes Responses endure longer than ionotropic on SCAG

GPCR structure:

Seven transmembrane spanning receptor

What happens when neurotransmitter binds to GPCR?

Activates a G protein complex (heterotrimer) composed of an alpha (α), beta (β), and gamma (γ) subunit, by facilitating the exchange of GDP for GTP in the α subunit

Activated G protein stimulates what?

enzymes that control the levels of second messengers, e.g., cyclic AMP, cyclic GMP, diacylglycerol, Ca2+

Second messengers do what?

Open or close ion channels, activate kinase enzymes, phosphorylate channel proteins, activate or inactivate genes

G protein activation step 1:

NT binds to a GPCR (which is a guanine nucleotide exchange factor, GEF) which binds to the G protein complex—GDP releases from α subunit

G protein activation step 2:

α subunit binds GTP and recruits downstream effectors

G protein activation step 3:

GTP is hydrolyzed by a GTPase activating protein (GAP)

G protein activation step 4:

the inactive, GDP-bound state

The most common alpha (α) subunits are:

Gαi Gαq

Gαs function:

stimulates Adenylyl cyclases that convert ATP to cAMP → increases cAMP → activates protein kinase A (PKA) → phosphorylates substrates

Gαi function:

inhibits adenylyl cyclases → decreases cAMP → decreases PKA activation

Gαq function:

stimulates phospholipase Cβ (PLC) → cleaves PIP2 into DAG and IP3 DAG activates PKC IP3 opens Calcium channels releasing Ca2+

Proteins are regulated by what?

phosphorylation

Kinases are:

phosphorylating enzymes – take a PO4 group from ATP and transfer it to a protein

Phosphatases are:

dephosphorylating enzymes – remove PO4 groups from proteins

Acetylcholine Receptors:

NG NM NN M1 M3 M5 M2 M4

Adrenergic Receptors:

α1A β1 β2 β3 α1B α1D α2A α2B α2C

Cholinergic receptors classes:

Nicotinic receptors and Muscarinic receptors

Nicotinic receptors:

excitatory, widespread throughout the body, e.g., they are on the ganglia (Adrenal Medulla expresses Nicotinic receptors)

Muscarinic receptors:

inhibitory or excitatory depending on subtype, cell type/tissue, etc. – widespread throughout the body

Nicotinic receptors are what type of receptors? (PNS + SNS)

excitatory ionotropic receptors composed of five subunits that form the receptor and ion pore (FAST = ion channel = ganglia)

Nicotinic receptors are permeable to: (PNS + SNS)

Na+, K+, and for some subtypes Ca++

Three families of nicotinic receptors: (PNS + SNS)

Ganglion type “NG” Neuronal type “NN” Neuromuscular type “NM”

NG nicotinic receptors location: (PNS + SNS)

ganglia

NM nicotinic receptors location: (Somatic)

at the NMJ

The effect of ACh at nicotinic receptors is: (PNS + SNS)

always stimulatory

Muscarinic receptors are: (PNS)

GPCRs that generate PNS effects SSLUDDD-C (GPCR = organs SCAG)

Muscarinic receptors are located on: (PNS)

SCAG

Five muscarinic receptor subtypes: (PNS)

M1 M2 M3 M4 M5

M1 M3 M5 couple to: (PNS)

Gαq stimulate PLC which leads to increased Ca++ production and release = stimulatory (M1/3/5 = Gq = ↑ Ca²⁺)

M2 M4 couple to: (PNS)

Gαi inhibit adenylyl cyclases which decrease cAMP production = generally inhibitory (M2/4 = Gi = ↓ cAMP)

Acetylcholine receptors think: (PNS)

PARASYMPATHETIC (SSLUDDD-C)

Location of nicotinic receptors: (PNS + SNS)

All ganglia Hormone-producing cells of adrenal medulla Skeletal muscle NMJ Brain

Myasthenia Gravis is: (Somatic NM receptor disease)

autoimmune destruction of NM-type nicotinic receptors

Pyridostigmine (Mestinon): (PNS ↑)

treats Myasthenia Gravis Acetylcholinesterase inhibitor increases ACh

Varenicline (Chantix): (CNS nicotinic)

smoking cessation nicotinic receptor agonist (partial)

Nicotine (Nicorette): (CNS nicotinic)

smoking cessation nicotinic receptor agonist

Why nicotine drugs do not cause extreme skeletal muscle contraction:

has affinity of neuronal type rather than muscle type

Muscarinic receptor activation causes: (PNS)

SSLUDDD-C

Natural muscarinic receptor antagonists: (block PNS)

Datura stramonium Hyoscyamus niger Atropa Belladonna

Examples of muscarinic antagonists: (block PNS)

atropine scopolamine

Alpha (α1) receptors: (SNS)

Gq → vasoconstriction (α1 = constrict)

Prazosin (Minipress): (SNS blocker)

α1 adrenergic antagonist decreases contraction of vascular smooth muscle relaxes blood vessels and decreases BP

Alpha (α2) receptors: (SNS)

Gi → decrease cAMP inhibits NE release (α2 = shut OFF SNS)

α2A receptor: (SNS)

presynaptic inhibits NE release decreases SNS outflow hypotension sedation analgesia

α2B receptor: (SNS)

postsynaptic causes smooth muscle contraction

α2C receptor: (SNS)

presynaptic inhibits catecholamine release from adrenal medulla

Clonidine (Catapres): (SNS ↓)

α2 adrenergic agonist centrally acting reduces sympathetic outflow decreases NE

Lofexidine (Lucemyra): (SNS ↓)

α2 adrenergic agonist dampens SNS activity treats opioid withdrawal

Beta (β) receptors: (SNS)

Gαs → increase cAMP (β = stimulate via cAMP)

Nicotinic receptors memory hack:

FAST = ion channel = ganglia

Muscarinic receptors memory hack:

GPCR = organs (SCAG)

M1 M3 M5 memory hack:

Gq = ↑ Ca2+ = stimulate

M2 M4 memory hack:

Gi = ↓ cAMP = inhibit

Alpha 1 (α1) memory hack:

constrict

Alpha 2 (α2) memory hack:

shut OFF SNS

Beta (β) memory hack:

stimulate via cAMP

Darifenacin (Enablex)

◦ Treats overactive bladder

◦ Muscarinic receptor antagonist

Methacholine (Provocholine)

◦ Test for the diagnosis of bronchial airway hyperreactivity

◦ Muscarinic receptor agonist

Cobnefy

Xanomeline

◦ Centrally-acting muscarinic receptor agonist (thought to work through M1 and M4)

combined with

Trospium

◦ Peripherally-restricted muscarinic receptor antagonist to block xanomeline’s “SLUDDD-C” effects.

Approved to treat schizophrenia

The first non-dopaminergic drug for schizophrenia! Approved

September 26, 2024

Trospium

◦ Peripherally-restricted muscarinic receptor antagonist to block xanomeline’s “SLUDDD-C” effects.

◦ Treats overactive bladder

◦ Muscarinic receptor antagonist

Xanomeline

◦ Centrally-acting muscarinic receptor agonist (thought to work through M1 and M4)

Guanfacine (Tenex)

◦ Anti-hypertensive

◦ a2 adrenergic agonist, centrally-acting

◦ Reduces sympathetic outflow that leads to decreased release of NE on smooth muscles

and heart

M1 receptor (PNS)

Secretion: Tears (Lacrimal glands) and Saliva (salivary glands) expressed on glands “G”

M2 receptor (PNS)

Slow Heart Rate: SA/AV nodes negative chronotropic effect expressed on cardiac muscle “C”

M3 receptor (PNS)

Secretion and Smooth Muscle Contraction: Every PNS effect except on the heart expressed on smooth muscle “S” and glands “G” M3 also causes SNS-mediated sweating from sweat glands “G”

α2A receptor (SNS)

in periphery and brain pre-synaptic inhibits NE release in brain and from SNS fibers inhibits SNS outflow hypotension sedation anesthesia analgesia reduction of symptoms of opioid withdrawal CNS mediated also targets of ADHD medications like guanfacine

α2B receptor (SNS)

mostly in periphery post-synaptic causes α2-induced smooth muscle cell contraction via Gi mechanism

α2C receptor (SNS)

in periphery and brain presynaptic inhibits release of catecholamines from the adrenal medulla also targets of ADHD medications like guanfacine

α1A receptor (SNS)

Bladder neck prostate contracts bladder sphincter and prostate

α1B receptor (SNS)

Heart arteriole smooth muscle most abundant subtype in heart predominant receptor causing contraction of vascular smooth muscle vasoconstriction of many arteries and veins promotes cardiac growth and structure

α1D receptor (SNS)

Aorta and coronary arteries predominant receptor causing vasoconstriction in aorta and coronary arteries

Sympathomimetics (Constricts “S” in SCAG)

Drugs that Mimic the SNS:

• Methamphetamine- stimulates release of NE (and DA)

• Propylhexedrine (Benzedrex)-stimulates release of NE (and DA)

• Pseudoephedrine - stimulates the release of NE

• Sinus Congestion Relief