ADCYs

ADCYs refers to the adenylate cyclase gene family, a group of enzymes that produce cyclic AMP (cAMP) from ATP, a central step in many signaling pathways. cAMP acts as a second messenger that activates downstream effectors such as protein kinase A (PKA) and Epac, thereby regulating diverse cellular processes including metabolism, ion transport, gene expression, and neuronal signaling.

In humans, the ADCY family includes nine membrane-bound adenylate cyclases (ADCY1–ADCY9) and one soluble form (ADCY10, often called soluble adenylyl cyclase or sAC). The membrane-bound isoforms are integral membrane proteins with multiple transmembrane segments and cytosolic catalytic domains. The two catalytic regions, termed C1 and C2, come together to form the active site that converts ATP to cAMP. The soluble form lacks the transmembrane segments and is distributed in the cytosol, mitochondria, and other compartments; it is regulated by intracellular calcium and bicarbonate, among other factors, making it a metabolic sensor in some contexts.

Regulation of ADCYs is diverse. Membrane-bound ADCYs are typically regulated by heterotrimeric G proteins (Gs stimulates, Gi inhibits) and by other signals such as Ca2+/calmodulin; many isoforms can be directly activated by forskolin. sAC is regulated primarily by bicarbonate, Ca2+/calmodulin, and cellular energy state. The produced cAMP acts locally and globally, shaping signaling networks in a tissue- and context-dependent manner.

ADCYs are widely expressed and isoform-specific, contributing to specialized cAMP signaling in different tissues, including the brain, heart, sensory systems, and metabolism. Variants and dysregulation of ADCY genes have been linked to various human conditions, with ADCY5-related dyskinesia being among the best characterized examples. Research continues to elucidate the precise roles of individual ADCYs in health and disease.