adrenergic and cholinergic receptors

M1

§  Location: nerves

§  G-protein subtype: Gq

§  Post-receptor mechanism: IP3/DAG cascade

M3

§  Location: glands, smooth muscle, endothelium

§  G-protein subtype: Gq

§  Post-receptor mechanism: IP3/DAG cascade

M5

§  Location: CNS

§  G-protein subtype: Gq

§  Post-receptor mechanism: IP3/DAG cascade

M2

§  Location: nerves, smooth muscle, heart

§  G-protein subtype: Gi

§  Post-receptor mechanism: inhibition of cAMP and activation of K+ channels

M4

§  Location: CNS

§  G-protein subtype: Gi

§  Post-receptor mechanism: Inhibition of cAMP

NM

§  Location: skeletal muscle NMJ

§  Subunit type: pentamer ( 2 alpha, beta, delta, gamma)

§  Post-receptor mechanism: Na+, K+ depolarizing ion channel

NN

§  Location: CNS, postganglionic cell bodies, dendrites

§  Subunit type: pentamer with only alpha or beta subunits: CNS (2 alpha, 3 beta), Ganglia ( 2 different alpha and 3 beta)

§  Post-receptor mechanism: Na+, K+ depolarizing ion channel

A1

Post synaptic; can be a target for endogenous catecholamines (ex. NE and E), direct acting (ex. Prazosin), indirect acting (ex. Cocaine) medications

A2

pre-synaptic and usually inhibitory in nature; targeted by endogenous catecholamines, direct (ex, clonidine) or indirect medications

Beta

are stimulatory (G_s) and targets for endogenous catecholamines direct (dobutamine, propranolol) or indirect medications

Bethanechol

o   Direct acting cholinergic agonist

o   Directly and preferentially binds to muscarinic receptors

o   Resistant to hydrolysis by AChesterase

o   Widely used to treat atonic (lacking muscular tone) disorders in GI and urinary tract

o   How it works

§  GI and urinary tracts contain both M2 and M3 receptors

§  M3 receptors are Gq and initiate signal transduction changes through IP3/DAG activation

§  IP3 -> increases intracellular Ca2+ which induces smooth muscle contraction via myosin light chain kinase (MLCK)

Pilocarpine

o   Direct acting cholinergic agonist

o   Directly stimulates muscarinic receptors

o   Used systemically to increase salivary gland secretion

o   Used in the eye to cause miosis (contraction of the iris sphincter), cause a loss of accommodation (constriction of the ciliary muscle), and lowering intraocular pressure

o   M₃R on salivary gland acinar cells -> GqPCR -> Increased IP3 and DAG

§  IP3 binds to IP3 receptors on the endoplasmic reticulum -> increased Ca²⁺

·       Then elevated Ca²⁺ activates Cl- channels in acinar cells

·       Cl- is secreted into lumen gland and Na+ and H2O follow -> fluid secretion

§  MLCK can cause contraction to expel saliva from cells

Donepezil

o   Indirect acting/acetylcholinesterase inhibitor

o   Reversible, non-competitive inhibitor of acetylcholinesterase

o   In Alzheimer’s there is a loss of cholinergic neurons in the brain

§  No neurons-> no ach release -> no cholinergic signaling

o   How it works

§  Inhibition of AChE allows remaining acetylcholine to bind to CNS cholinergic receptors

§  ACH can remain at the synapse or diffuse away (still in its active form) to target other receptors

Pyridostigmine

o   Indirect acting/acetylcholinesterase inhibitor

o   Quarternary ammonium compound (has permanently charged nitrogen atom) -> remains in the periphery (cannont enter CNS because of charge)

o   Inhibits acetylcholinesterase

o   Used for the treatment of myasthenia gravis, a disorder of the NMJ

§  Characterized by weakness and fatigability

§  Caused by an autoimmune reaction of the nicotinic receptors at the NMJ

Atropine

o   Antimuscarinic agent

o   can be administered systemically or opthalmically to block actions of Ach in smooth muscle, secretory glands, the eye, and the CNS

o   reverses muscarinic effects by competitively binding to muscarinic receptors (but non-selective to M1-M5)

§  reversible and surmountable blockade

§  used to reverse symptoms of cholinergic poisoning

·       helpful to reverse brachycardia and bronchoconstriction relatively quickly

§  has no effect at the nicotinic receptors

Scopolamine

o   Antimuscarinic agent

o   Blocks the actions of Ach in smooth muscle, secretory glands, and the CNS

o   Reverse muscarinic effects by competitively binding to muscarinic receptors (but non-selective to M1-M5)

§  May also bind to serotonin 5HT3 receptors (predominately found in the chemoreceptor trigger zone; vomiting reflex center)

o   Used predominately for reduction of motion sickness and post-operative GI upset

§  Injection or patch

§  Most unpleasant side effect: dry mouth

Phenylephrine

o   Direct alpha 1 adrenergic agonist

o   Produces arterial vasoconstrivtion

GqPCR -> increased IP3 -> increased Ca²⁺ -> increased MLCK activity

Clonidine

o   Direct acting Alpha 2 adrenergic agonist

o   Stimulates Alpha 2 GiPCRS in the brain stem -> reduces NE signaling

§  Indication: reduces blood pressure and is also used in ADHD, but mechanism is not well understood

Albuterol

o   Direct acting beta2 adrenergic agonist

o   Selective for Beta 2 reptors (therefore little effect on heart)

§  B2R are GsPCR

o   Relaxes bronchiole smooth muscle

o   How it works

§  GsPCR -> increased AC -> increased cAMP -> protein kinase A (amongst others)

§  Elevated PKA -> reduction in intracellular Ca²⁺ -> reduction in MLCK -> relaxation of bronchial smooth muscle

§  Bronchodilation

Propranolol

o   Non-selective beta-adrenergic antagonist

o   Blocks both B1 and B2 receptors -> decreases in heart rate, cardiac contractility, blood pressure and myocardial oxygen demand

o   In the absence of antagonist- NE would bind to B1 or B2 -> increased PKA -> increased CA2+ -> or MLCK inhibition

§  In the absence of antagonist heart rate, contractility and conduction would be faster or elevated

o   In the presence of antagonist- decreased PKA -> decreased Ca+2 -> or reduced MLCK inhibiton

§  In the presence of antagonist heart rate, contractility and conduction would be slower or reduced