Motor Dysfunction in Type 5 Adenylyl Cyclase-null Mice

Tamio Iwamoto,Satoshi Okumura,Kousaku Iwatsubo,Jun-Ichi Kawabe,Koji Ohtsu,Ikuko Sakai,Yoko Hashimoto,Aki Izumitani,Kazunori Sango,Kyoko Ajiki,Yoshiyuki Toya,Satoshi Umemura,Yoshio Goshima,Nobutaka Arai,Stephen F Vatner,Yoshihiro Ishikawa

doi:10.1074/jbc.c300075200

Abstract

Various neurotransmitters, such as dopamine, stimulate adenylyl cyclase to produce cAMP, which regulates neuronal functions. Genetic disruption of the type 5 adenylyl cyclase isoform led to a major loss of adenylyl cyclase activity in a striatum-specific manner with a small increase in the expression of a few other adenylyl cyclase isoforms. D1 dopaminergic agonist-stimulated adenylyl cyclase activity was attenuated, and this was accompanied by a decrease in the expression of the D1 dopaminergic receptor and G(s)alpha. D2 dopaminergic agonist-mediated inhibition of adenylyl cyclase activity was also blunted. Type 5 adenylyl cyclase-null mice exhibited Parkinsonian-like motor dysfunction, i.e. abnormal coordination and bradykinesia detected by Rotarod and pole test, respectively, and to a lesser extent locomotor impairment was detected by open field tests. Selective D1 or D2 dopaminergic stimulation improved some of these disorders in this mouse model, suggesting the partial compensation of each dopaminergic receptor signal through the stimulation of remnant adenylyl cyclase isoforms. These findings extend our knowledge of the role of an effector enzyme isoform in regulating receptor signaling and neuronal functions and imply that this isoform provides a site of convergence of both D1 and D2 dopaminergic signals and balances various motor functions.

Highlights

The neurotransmitter dopamine acts through various dopaminergic receptor subtypes that are associated with either stimulation or inhibition of adenylyl cyclases (ACs),1 leading to the regulation of physiological functions such as the control of various motor functions or psychomotor activity [1]
Locomotor activity was attenuated and restored by selective D1 dopaminergic stimulation, suggesting that this dopaminergic signal targets AC5. Both dopaminergic signals may be able to couple to other AC isoforms as well because D1 or D2 dopaminergic stimulation could restore specific motor function, i.e. coordination or locomotion, respectively
Such selective dopaminergic agonist stimulation could not restore all of the motor disorders, indicating that AC5 is essential in balancing and maintaining both coordination and locomotion and may provide the site of convergence of both D1 and D2 dopaminergic signals

Summary

Introduction

The neurotransmitter dopamine acts through various dopaminergic receptor subtypes that are associated with either stimulation or inhibition of adenylyl cyclases (ACs),1 leading to the regulation of physiological functions such as the control of various motor functions or psychomotor activity [1]. D1 dopaminergic agonist-stimulated adenylyl cyclase activity was attenuated, and this was accompanied by a decrease in the expression of the D1 dopaminergic receptor and Gs␣.

Results

Conclusion