Signal Transduction Pathways

Like other G protein-coupled receptors, dopamine receptors transduce their signals through second messengers regulated by G proteins. In general, D1-like receptors stimulate adenylate cyclase via the Gs, and the D2-like receptors inhibit adenylate cyclase through the Gi. The signaling cascade is initiated by dopamine binding to the extracellular portion of the receptor. The binding of dopamine alters the receptor so that it activates a G protein present on the intracellular face of the neuron cell membrane. Once activated, G proteins modulate adenylate cyclase activity. G proteins bind guanosine triphosphate (GTP) or guanosine diphosphate (GDP). Dopamine binding to its receptor causes GDP to be replaced with GTP. Then, in the case of the D1-like receptors, a GTP-Gs complex is formed and associates with the catalytic subunit of adenylate cyclase, stimulating the conversion of ATP to cyclic (AMP) adenosine monophosphate. The GTP-Gs protein and the catalytic subunit of adenylate cyclase together constitute the active form of adenylate cyclase. The association of the G protein with the catalytic subunit of the cyclase also results in the hydrolysis of GTP to GDP. This hydrolysis causes the G protein to dissociate from the catalytic subunit and to reassociate with the receptor. This reaction terminates the synthesis of cyclic AMP. Therefore, the duration of cyclic AMP synthesis is regulated by GTPase activity. In the case of the D2-like receptors, receptor activation causes GTP binding to Gi, and this complex inhibits cyclase activity.

It should also be noted that several other second messenger systems are involved in D2-like receptor-mediated signal transduction, such as the stimulation of aracadonic acid metabolism and the activation of potassium channels.

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