Type 5 adenylyl cyclase is obligatorily required for the function of D2 dopamine receptor, but not of D1 and A2A receptors in corpus striatum

초록

The type 5 adenylyl cyclase (AC5, also called ACV) is a member of adenylyl cyclase(AC) superfamily that includes, to date, 9 types in mammals. The AC5 has been proposed to be a key component of dopamine receptor signaling on the basis that AC5 was preferentially expressed in the striatum where dopamine receptors were enriched. The integrity of the AC subtype that is coupled to specific dopamine receptor isoforms, however, has not been verified yet. In addition, understanding the in vivo role of AC5 has been hampered by unavailability of AC5 specific inhibitors. Consequently receptor-effector interaction including signal sorting has been a hiatus in dopamine receptor signaling framework. To specify the in vivo role of AC5, we generated and studied mice deficient for the AC5 gene. AC5 was the major AC in the striatum and played as the primary effector for multiple receptors including D1, D2, and A2A. AC5 was the mandatory effector for D2 receptor signaling, but not for D1 and A2A receptor functions. AC5 was shown to be a critical neuronal component for the action of the antipsychotic drugs, and mutant animals did not display Parkinsonian phenotypes despite of the deficit in D2/AC5 coupling.