Figure 2.

Cholinergic signaling via nAChRs and muscarinic acetylcholine receptors (mAChRs) regulates striatal function. (A) Diagrammatic representation of the primary striatal neurotransmitter systems. Cholinergic interneurons are the primary source of striatal acetylcholine (ACh) and regulate its function via pre-and post-synaptic nAChRs and muscarinic receptors. Acetylcholine regulates the activity of direct and indirect GABAergic medium spiny neurons (MSNs) by acting at α4β2* nAChRs, as well as M1 and/or M4 muscarinic receptors. In addition, acetylcholine modulates striatal dopamine (DA) release via an interaction at α6β2* and α4β2* nAChRs along with M2 and/or M4 muscarinic receptors on nigrostriatal dopaminergic and serotonergic (5-HT) terminals, which further regulates the output of direct and indirect pathway MSNs. Likewise, acetylcholine can modulate GABAergic interneuron activity via α7 and α4β2* nAChRs, as well as M2 muscarinic receptors. Acetylcholine can further control striatal function via α7 nAChRs and M2 and M3 muscarinic receptors located on the excitatory glutamatergic (GLU) inputs arising from the cortex. (B) Molecular signaling modulated by nAChRs. Stimulation of nAChRs increases intracellular Ca2+ which promotes activation of PKA and CAMKII to initiate ERK1/2 cascade activity. nAChR signaling can also occur via Ca2+ -independent mechanisms thru the JAK2/STAT3 pathway. (C) Molecular signaling via mAChRs. These receptors are coupled to G proteins. M2 and M4 receptors couple preferentially to Gi/0, whereas M1, M3 and M5 receptors mainly couple to Gq/11. Upon stimulation, M2 and M4 receptors inhibit adenylyl cyclase (AC) activity, leading to a decrease in intracellular cAMP levels and PKA activity to ultimately regulate ERK1/2 activity. M1, M3, and M5 receptors activate PKC by means of upstream PLC activation and increase in IP3 and Ca2+ levels. PKC activity leads to the activation of the MAP kinase cascade and ERK1/2.