Impaired D2 dopamine receptor function in mice lacking type 5 adenylyl cyclase

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Dopamine (D1, D2) and adenosine (A2A) receptors in the brain's striatum modulate cell signaling via adenylyl cyclases (ACs).
• The specific AC isoforms coupled to these receptors in vivo remain unidentified.
• Adenylyl cyclase type 5 (AC5) is highly expressed in the striatum, suggesting a key role.

Purpose of the Study:

• To investigate the in vivo function of adenylyl cyclase type 5 (AC5) in the striatum.
• To determine the role of AC5 in integrating signals from dopamine and adenosine receptors.
• To elucidate the involvement of AC5 in the mechanism of action of antipsychotic drugs.

Main Methods:

• Generation of AC5-deficient (AC5-/-) mice.
• Measurement of adenylyl cyclase activity in striatal tissue.
• Assessment of behavioral responses to receptor agonists and antipsychotic drugs.

Main Results:

• Genetic ablation of AC5 significantly reduced forskolin- and agonist-stimulated AC activity in the striatum.
• D1 and A2A receptor-mediated behaviors were largely preserved in AC5-/- mice.
• D2 receptor-mediated signaling to AC was abolished in AC5-/- mice, and antipsychotic drug effects on motor activity were altered.

Conclusions:

• AC5 is the principal adenylyl cyclase integrating signals from D1, D2, and A2A receptors in the striatum.
• The AC5 signaling cascade is essential for the neuroleptic effects of antipsychotic drugs.
• AC5 plays a critical role in striatal dopamine and adenosine receptor signaling pathways.