M

590 aa lq 43-44

CNS; Most abundant in cerebral cortex, hippocampus and striatum Autonomic ganglia Glands (gastric and salivary) Enteric nerves

Widely expressed in CNS, heart, smooth muscle, autonomic nerve terminals

Widely expressed in CNS (< than other mAChRs)

Abundant in smooth muscle and glands

Activation of PLC; TlP3 and TDAG ^ TCa2+ and PKC Depolarization and excitation (TsEPSP) Activation of PLD2, PLA2; TAA Couples via Gq/11

Inhibition of adenylyl cyclase, icAMP Activation of inwardly rectifying

K+ channels Inhibition of voltage-gated Ca2+ channels Hyperpolarization and inhibition Couples via Gi/Go (PTX-sensitive)

Activation of PLC; TlP3 and TDAG ^ TCa2+ and PKC Depolarization and excitation (TsEPSP) Activation of PLD2, PLA2; TAA Couples via Gq/11

Increased cognitive function (learning and memory) Increased seizure activity

Decrease in dopamine release and locomotion Increase in depolarization of autonomic ganglia Increase in secretions Heart:

SA node: slowed spontaneous depolarization; hyperpolarization, iHR

AV node: decrease in conduction velocity Atrium: i refractory period, i contraction Ventricle: slight i contraction Smooth muscle: T Contraction Peripheral nerves:

Neural inhibition via autoreceptors and heteroreceptor i Ganglionic transmission CNS: Neural inhibition

T Tremors; hypothermia; analgesia Smooth muscle

T Contraction (predominant in some, e.g. bladder) Glands:

T Secretion (predominant in salivary gland)

(Continued)

Characteristics of Muscarinic Acetylcholine Receptor Subtypes (mAChRs) (Continued)

Receptor

Size; Chromosome Location

Cellular and Tissue Location

Cellular Response*

Functional Response*

Heart

M4 479 aa Preferentially expressed in

11p 12-11.2 CNS, particularly forebrain

M5 532 aa Expressed in low levels in

15q 26 CNS and periphery

Predominant mAChR in dopamine neurons in VTA and substantia nigra

Inhibition of adenylyl cyclase, icAMP Activation of inwardly rectifying K+ channels

Inhibition of voltage-gated Ca2+ channels Hyperpolarization and inhibition Couples via Gi/Go (PTX-sensitive)

Activation of PLC; TlP3 and TDAG ^

TCa2+ and PKC Depolarization and excitation (TsEPSP) Activation of PLD2, PLA2; TAA Couples via Gq/11

Increases food intake, body weight, fat deposits Inhibition of dopamine release Synthesis of NO Autoreceptor- and heteroreceptor-mediated inhibition of transmitter release in CNS and periphery Analgesia; cataleptic activity Facilitation of dopamine release

Mediator of dilation in cerebral arteries and arterioles (?) Facilitates dopamine release Augmentation of drug-seeking behavior and reward (e.g., opiates, cocaine)

*Most organs, tissues, and cells express multiple mAChRs.

iM1, M3, and M5 mAChRs appear to couple to the same G proteins and signal through similar pathways. Likewise, M2 and M4 mAChRs couple through similar G proteins and signal through similar pathways.

^Despite the fact that in many tissues, organs, and cells multiple subtypes of mAChRs coexist, one subtype may predominate in producing a particular function; in others, there may be equal predominance.

ABBREVIATIONS: PLC, phospholipase C; IP3, inositol-1,4,5-trisphosphate; DAG, diacylglycerol; PLD2, phospholipase D; AA, arachidonic acid; PLA, phospholipase A; cAMP, cyclic AMP; SA node, sinoatrial node; AV node, atrioventricular node; HR, heart rate; PTX, pertussis toxin; VTA, ventral tegmentum area.

Following activation by agonists, mAChRs can be phosphorylated by a variety of receptor kinases and second-messenger regulated kinases; the phosphorylated mAChR subtypes then can interact with b-arrestin and presumably other adaptor proteins. As a result, the various mAChR signaling pathways may be differentially altered, leading to short- or long-term desensitization of a particular signaling pathway, receptor-mediated activation of the MAP kinase pathway downstream of mAChR phosphorylation, and long-term potentiation of mAChR-mediated PLC stimulation. Agonist activation of mAChRs also may induce receptor internalization and down-regulation.

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