Transducing emotionality: the role of adenylyl cyclases.

p t a V arious psychiatric disorders, including depression, anxiety, and other mood disorders, as well as responses to addictive drugs, have been linked to malfunctions of receptors coupled to the cyclic adenosine monophosphate (AMP) second-messenger signaling system and/or malfunction of downstream mediators such as protein kinase A (PKA) and the transcription factor cyclic AMP response element– binding protein. What has generally been largely ignored are the enzymes that generate cyclic AMP, the family of adenylyl cyclases (ACs). There are nine isoforms of membrane-bound adenylyl cyclase, and one soluble isoform of the enzyme (1). The activation of the membrane-bound isoforms is regulated by receptors via heterotrimeric G proteins (e.g., Gs ); however, various isoforms display additional patterns of regulation by Gi , G , and other factors such as Ca , calmodulin, and proein kinases. The AC family has been classified into four categories, ased on differential patterns of regulation (e.g., Ca /calmodulin timulation, G stimulation, Gi inhibition, Ca inhibition, etc.). There are also other regulators of specific isoforms of adenylyl cyclase, including RGS2 (regulator of G protein signaling 2); Snapin, a member of the SNAP-25/Snare complex; Ric-8, a guanine nucleotide exchange protein; and the PKA scaffolding protein, AKAP 79 (1). Although the expression patterns (tissue and brain regional localization) of the various AC isoforms play a role in dictating their specificity in affecting physiological processes, clearly the diverse regulatory control of ACs places them in a position to integrate signaling that is initiated by activation of cellular receptors. For instance, the group II ACs, which include AC2, AC4, and AC7, are conditionally activated by G : when enzyme activity is stimulated through receptor-coupled Gs , the activity can be enhanced 5to 10-fold by G , although G has no effect alone. Therefore, when G is released as a result of activation of Gi/Go-coupled receptors, AC2 and AC7 are synergistically stimulated in the presence of Gs , facilitating cross talk between G protein– coupled receptors. For example, depending on receptor colocalization, activation of D1 (Gs -coupled) and 5-hydroxytryptamine2 (Gi -coupled) receptors can result in synergistic activation of AC7 via the interaction of Gs and G with this isoform, but a similar activation of D1 and 5-hydroxytryptamine2 receptors in a cell expressing AC5 would produce an inhibition of activated AC5 by Gi . AC7 activity is also modulated by phosphorylation via the isoform of protein kinase C (2). Overall, the specific regulation of AC isoforms can modulate the levels and possibly cellular localization of cyclic AMP, such that the production of and response to cyclic AMP in a given cell are fine-tuned for modulation of downstream signaling pathways (1). All of the AC isoforms are expressed in brain, some localized to particular regions, and some more widespread (1). Given their key roles in neurotransmitter signaling, leading to modification of neuronal activity, they have been investigated with respect to psychiatric disorders. The paper by Joeyen-Waldorf et al. (3) focuses on the AC7 isoform as a player in the genetic vulnerability to major depres-