Motor Dysfunction in Type 5 Adenylyl Cyclase-null Mice

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 ␣. 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.

Golgb1 regulates protein glycosylation and is crucial for mammalian palate development

“…Genomic PCR followed by Sanger sequencing confirmed that all three mutations were ENU induced and absent in the parental A/J and FVB/NJ strains. Because neither Itgb5 null mice nor Adcy5 null mice have palate defects (Huang et al, 2000;Iwamoto et al, 2003) and since ocd/ocd rats exhibit syndromic cleft palate associated with a Golgb1 disruption (Katayama et al, 2011), the Golgb1 ivs9+1G>A mutation became a prime candidate for causing cleft palate in the ENU1483 mice.…”

ADCY5 -related dyskinesia

“…ADCY5 is highly expressed in striatum, a region involved in modulating movement, and ADCY5 knock-out mice display a parkinsonian phenotype. 4 Overexpression of either mutated protein in HEK293 cells increased cAMP accumulation, 2 suggesting a gain-offunction effect.…”

Discovery of Novel Adenylyl Cyclase Inhibitor by Cell-Based Screening

“…7) Deficiency of type 1 AC up-regulates the resistance to glutamate-induced neurotoxicity in the nervous system, 20) and β-adrenergic receptor stimulation-induced myocyte apoptosis in the heart is attenuated in type 5 AC knockout mice. 6,21) Hence, compound 1 is expected to be a leading compound for developing medicines for above-mentioned conditions.…”

“…5) Deficiency of type 5 AC induces Parkinson's disease-like symptoms in mice; conversely, excitotoxicity of neurons is alleviated in type 1 AC knockout mice. 6) Furthermore, CREB activation is considered to be important in oncogenesis, 7) and some tumor cells show overexpression or constitutive activation of CREB. [8][9][10] These reports indicate that dysregulation of the AC/PKA/CREB pathway may induce neurodegenerative diseases and cancers, and the compounds that modulate the AC/PKA/CREB pathway are expected to be developed as medicines for these diseases.…”