Oligomerization of transmembrane adenylyl cyclase isoforms.

Membrane-bound adenylyl cyclases (ACs) function as vital enzymes that convert external signals into intracellular responses through the second messenger cAMP. Traditionally viewed as monomers, ACs are now recognized to form oligomers, introducing new regulatory mechanisms. This minireview synthesizes emerging structural and biochemical evidence for AC oligomerization and explores its functional significance. Oligomerization plays a critical role in the localization of ACs by regulating retention in the endoplasmic reticulum, membrane targeting, and distribution within signaling microdomains. Functional data suggest that dimer/oligomer interfaces act as regulatory nodes, although isoform-specific differences in oligomer architecture and functional consequences remain poorly understood. Defining the mechanisms underlying these differences is a critical area for future investigation. Importantly, the structural variability of oligomer interfaces, relative to conserved catalytic domains, offers new therapeutic potential that may enable isoform-selective modulation of AC activity. By integrating past and current research, this review frames oligomerization as a fundamental, yet underexplored, determinant of cAMP signaling. Advancing our understanding of the assembly, regulation, and dynamics of AC oligomers may open new avenues for precise control of cAMP signaling in both physiological and pathological contexts. SIGNIFICANCE STATEMENT: Oligomerization of membrane adenylyl cyclases adds regulatory complexity to cAMP signaling by modulating catalytic activity, localization, and compartmentalization. Distinct homo- and hetero-oligomers may underlie isoform-specific functions and offer new therapeutic opportunities.