Motor dysfunction in type 5 adenylyl cyclase-null mice.
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.
Iwamoto
Tamio
T
Department of Physiology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan.
Okumura
Satoshi
S
Iwatsubo
Kousaku
K
Kawabe
Jun-Ichi
J
Ohtsu
Koji
K
Sakai
Ikuko
I
Hashimoto
Yoko
Y
Izumitani
Aki
A
Sango
Kazunori
K
Ajiki
Kyoko
K
Toya
Yoshiyuki
Y
Umemura
Satoshi
S
Goshima
Yoshio
Y
Arai
Nobutaka
N
Vatner
Stephen F
SF
Ishikawa
Yoshihiro
Y
D000262:Adenylyl Cyclases / Q000235:genetics / Q000502:physiology*; D000818:Animals; D018491:Dopamine Agonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000201:enzymology / Q000209:etiology / Q000235:genetics; D011954:Receptors, Dopamine / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
D018491:Dopamine Agonists; D007527:Isoenzymes; D011954:Receptors, Dopamine; D000262:Adenylyl Cyclases; C419510:adenylyl cyclase type V