Exam 4 - Lecture 35, Cholinergic Agonists and Cholinesterase Inhibitors

Agonist at muscarinic receptors (M type GPCRs) Agonist at nicotinic receptors (nAChR ion channels)

Inhibitors of cholinesterase = increase ACh

Gaq Mechanism: IP3, DAG cascade

Gai/o Mechanism: Inhibition of cAMP production, activation of K+ channels

Gai/o Mechanism: Inhibition of cAMP production

Mechanism: Na, K depolarizing ion channel

Pentameric channel, conducting Na,K,CA2+ Activation of receptor depolarizes membrane potential, initiating action potentials in neurons and contraction of muscle Binding 1 ACh molecule results in modest increase in open probability; simultaneous binding gives significant increase in Po

Fetal (immature) channels Mature channels

consists of 2 X a1 subunits and one each of beta, delta, and gamma-subunits. This channel has low amplitude currents with long open time

Gamma subunits are replaced with E-subunits. Open time decreases but current amplitude increases

some isoforms are pentamer of a7-subunits activations results in fast, rapidly decaying currents

Desensitize Increase in Ca2+ will cause an increase in PKC (phosphorylates proteins that facilitate Desensitization of channels) Active -> Desensitization -> resting state

Ach will bind to receptor, activate channel and they will pass Na and depolarize membrane…leads to EPSP (if large enough) and it will cause action potential and contraction

• Activates PLCB • PLCB metabolizes PIP2 to DAG and IP3 • DAG activates PKC • IP3 activates IP3 receptors on ER • NOTE: decrease of PIP2 also has cellular effect (inhibition of M-current

• Gai inhibits Adenylate Cyclase -> decrease cAMP • Gbg activates GIRK channels, made of Kir3-subunits, increase K+ flux and decrease excitability • Gbg inhibits activity of specific Cav channels; decrease Ca2+ flux and decreasing excitability

Irreversible , covalent inhibitors of AChE most common type of chemical pesticide Ex. DDT, banned by most countries in 70s and 80s and superseded by parathion

DUMBBELSS D- diarrhea, defacation (muscarinic) U- Urination (M) M - Miosis (M) B - Bronchospasm (M) B - Bradycardia (M) E - Excitation (N...followed by block) L - Lacrimation (M) S - Salivation (M) S - Sweating (M)

Glaucoma Ileus or Urinary retention Myasthenia Gravis

often caused by high ocular pressure Drugs constriction pupil and ciliary muscle, increasing outflow of humor form eye and reducing ocular pressure

can occur after surgery or neurological injury

Autoimmune degradation of SM nAChRs, causing weakness treated with cholinesterase inhibitors Short acting (15 min, used to diagnose) Long-acting for treatment (4hr, neostigmine...8hr, pyridostigmine)

Used in treatment of Myasthenia graves Used to treat Ogilvile syndrome Used to treat envenomation from snake bite, particularly kraits

Reversible cholinesterase inhibitor Used to treat glaucoma and delayed gastric emptying, mydiasis Crosses BBB so can be used as antidote for OD with anticholinergics such as Atropine and Belladonna Can cause death by respiratory arrest and paralysis of cardiac muscle

Found in high conc at chemical synapses and neuromuscular junctions Required to terminate action of ACh Inhibitors augment the action of ACh so are cholinomimics Some AChE-inhibitors have medial utility, some are dangerous toxins