The M2 muscarinic receptors are located in the heart, where they act to slow the heart rate down to normal sinus rhythm after negative stimulatory actions of the parasympathetic nervous system, by slowing the speed of depolarization. They also reduce contractile forces of the atrial cardiac muscle, and reduce conduction velocity of the atrioventricular node (AV node). However, they have little effect on the contractile forces of the ventricular muscle, slightly decreasing force. Gi protein alpha subunit is a family of heterotrimeric G protein alpha subunits. This family is also commonly called the Gi/o (Gi /Go ) family or Gi/o/z/t family to include closely related family members. G alpha subunits may be referred to as Gi alpha, Gαi, or Giα. The general function of Gi/o/z/t is to activate intracellular signaling pathways in response to activation of cell surface G protein-coupled receptors (GPCRs). GPCRs function as part of a three-component system of receptor-transducer-effector. The transducer in this system is a heterotrimeric G protein, composed of three subunits: a Gα protein such as Giα, and a complex of two tightly linked proteins called Gβ and Gγ in a Gβγ complex. When not stimulated by a receptor, Gα is bound to GDP and to Gβγ to form the inactive G protein trimer.When the receptor binds an activating ligand outside the cell (such as a hormone or neurotransmitter), the activated receptor acts as a guanine nucleotide exchange factor to promote GDP release from and GTP binding to Gα, which drives dissociation of GTP-bound Gα from Gβγ. GTP-bound Gα and Gβγ are then freed to activate their respective downstream signaling enzymes. Gi proteins primarily inhibit the cAMP dependent pathway by inhibiting adenylyl cyclase activity, decreasing the production of cAMP from ATP, which, in turn, results in decreased activity of cAMP-dependent protein kinase. Inhibition of adenylyl cyclase leads to a decrease in intracellular cAMP levels. In SA node cells, cAMP normally activates protein kinase A (PKA), which phosphorylates If channels, increasing their activity and thereby promoting depolarization. With reduced cAMP levels and decreased PKA activity, If channels become less active. This results in slower and less frequent spontaneous depolarization of SA node cells. Slower depolarization leads to a longer time for the membrane potential to reach the threshold for firing an action potential. In summary, the Gi protein-mediated mechanism in cardiac muscle primarily involves the inhibition of adenylyl cyclase, leading to reduced cAMP levels and decreased PKA activity. This, in turn, inhibits the activity of If channels, which control the rate of spontaneous depolarization in SA node cells. As a result, the heart rate is reduced, allowing the parasympathetic nervous system to exert control over heart rate regulation.

Gi Muscarinic Cardiac Muscle Contraction References