Impaired D2 Dopamine Receptor Function in Mice Lacking Type 5 Adenylyl Cyclase

Abstract

Dopamine receptor subtypes D1 and D2, and many other seven-transmembrane receptors including adenosine receptor A2A, are colocalized in striatum of brain. These receptors stimulate or inhibit adenylyl cyclases (ACs) to produce distinct physiological and pharmacological responses and interact with each other synergistically or antagonistically at various levels. The identity of the AC isoform that is coupled to each of these receptors, however, remains unknown. To investigate the in vivo role of the type 5 adenylyl cyclase (AC5), which is preferentially expressed in striatum, mice deficient for the AC5 gene were generated. The genetic ablation of the AC5 gene eliminated >80% of forskolin-induced AC activity and 85-90% of AC activity stimulated by either D1 or A2A receptor agonists in striatum. However, D1- or A2A-specific pharmaco-behaviors were basically preserved, whereas the signal cascade from D2 to AC was completely abolished in AC5(-/-), and motor activity of AC5(-/-) was not suppressed by treatment of cataleptic doses of the antipsychotic drugs haloperidol and sulpiride. Interestingly, both haloperidol and clozapine at low doses remarkably increased the locomotion of AC5(-/-) in the open field test that was produced in part by a common mechanism that involved the increased activation of D1 dopamine receptors. Together, these results suggest that AC5 is the principal AC integrating signals from multiple receptors including D1, D2, and A2A in striatum and the cascade involving AC5 among diverse D2 signaling pathways is essential for neuroleptic effects of antipsychotic drugs.

Stimulation of Adenosine Receptors Selectively Activates Gene Expression in Striatal Enkephalinergic Neurons

“…In any case, the main isoform of adenylyl cyclase in the striatum is AC5, and co-stimulation of G s -and G i -coupled receptors shows antagonistic interactions at the AC5 level (Chern, 2000;Defer et al, 2000). In fact, D 2 receptor stimulation has been shown to counteract cAMP accumulation induced by A 2A receptor stimulation in membrane preparations from mouse striatum (Lee et al, 2002).…”

“…A 2A and D 2 receptors exert reciprocal antagonistic interactions that modulate the function of GABAergic enkephalinergic neurons (Ferré et al, 1993(Ferré et al, , 1997Agnati et al, 2003) and recent studies have demonstrated the ability of A 2A and D 2 receptors to heteromerize Kamiya et al, 2003;Ciruela et al, 2004;Woods and Ferré, 2005). A 2A and D 2 receptors are prototypical G s -and G i -coupled receptors, respectively, which play opposite effects on adenylyl-cyclase (Kull et al, 1999;Hillion et al, 2002;Lee et al, 2002). Stimulation of A 2A receptors can potentially stimulate striatal adenylyl-cyclase, with the consequent activation of the cAMP-PKA signaling pathway and the induction of the expression of different genes, such as c-fos and preproenkephalin (Agnati et al, 2003;Ferré et al, 2003Ferré et al, , 2004.…”

Adenylyl cyclase type 5 (AC5) is an essential mediator of morphine action

“…Most are expressed in brain where they show distinct, although overlapping, expression patterns. The lack of specific inhibitors for these distinct forms of adenylyl cyclase has made it difficult to characterize the role each isoform plays in mediating the functions of opioid receptors.Adenylyl cyclase type 5 (AC5) is unique among these enzymes based on its considerable enrichment within the striatum, with lower levels seen in prefrontal cortex and certain other brain regions (15)(16)(17)(18). This enrichment in striatum is potentially important for opioid action, because , ␦, and opioid receptors are highly expressed in this brain region (8,19), where they are best implicated in regulating opioid reward: Activation of striatal and ␦ opioid receptors is rewarding, whereas activation of receptors opposes reward.…”

“…This enrichment in striatum is potentially important for opioid action, because , ␦, and opioid receptors are highly expressed in this brain region (8,19), where they are best implicated in regulating opioid reward: Activation of striatal and ␦ opioid receptors is rewarding, whereas activation of receptors opposes reward. Therefore, we investigated the physiological significance of AC5 in mediating the behavioral effects of morphine, as well as opioid receptor-mediated inhibition of adenylyl cyclase in striatum, by using recently developed AC5 Ϫ/Ϫ mice (18). increased these latencies, respectively, to 38.0 and 23.5 s at 52°C, and 27.8 and 17.7 s at 55°C (Fig.…”

Distribution, Elimination, and Rearrangement of Cyclic Volatile Methylsiloxanes in Oil-Contaminated Soil of the Shengli Oilfield, China

“…Dopamine has been demonstrated to affect brain neural architecture during development (Todd, 1992;Swarzenski et al, 1994;Song et al, 2002). Data described above indicate that brain levels of D5 in rats exposed to 160 ppm D5 were approximately twice as high as corresponding blood levels.…”