Adenylyl Cyclase Signaling Mechanisms in Mammalian Systems

Adenylyl cyclases (ACs) are pivotal enzymes that catalyse the conversion of ATP into cyclic adenosine monophosphate (cAMP), a second messenger fundamental to diverse physiological processes. In mammalian cells, nine membrane‐bound isoforms and one soluble isoform respond to extracellular cues via G protein‐coupled receptors (GPCRs) and other regulators. Upon ligand binding to GPCRs, the stimulatory G protein α subunit (Gαs) activates AC, elevating local cAMP concentrations. Conversely, inhibitory Gα subunits (Gαi/o) and Gβγ dimers can attenuate or modulate AC activity, providing nuanced bidirectional control. Beyond G proteins, AC regulation is further diversified by calmodulin binding to Ca2+‐sensitive isoforms, phosphorylation by protein kinases and direct lipid interactions within the transmembrane domains. High‐resolution structural studies have revealed the modular architecture of cytosolic catalytic domains (C1 and C2), their interfaces for nucleotide and activator binding, and the dynamic conformational changes that underpin enzyme activation and inhibition. These insights explain how AC isoforms integrate signals from hormones, neurotransmitters, metabolic cues and lipids to shape cAMP microdomains. The resulting cAMP gradient controls protein kinase A (PKA), exchange proteins directly activated by cAMP (EPACs) and cyclic nucleotide‐gated channels, thereby orchestrating gene expression, metabolism, synaptic plasticity and cardiac contractility. Dysregulation of AC signalling is implicated in cardiovascular disease, neurological disorders and metabolic syndrome, making ACs attractive therapeutic targets. Ongoing research seeks to exploit isoform‐selective modulation and to unravel non-canonical regulatory mechanisms that govern spatial and temporal control of cAMP signalling.

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Technical terms

cAMP: Cyclic adenosine monophosphate, a second messenger produced by adenylyl cyclase that activates downstream effectors such as PKA.

G protein-coupled receptor (GPCR): A membrane receptor that transduces extracellular signals through heterotrimeric G proteins to regulate intracellular effectors.

Gαs and Gαi/o: Stimulatory and inhibitory α subunits of G proteins; Gαs enhances adenylyl cyclase activity, whereas Gαi/o attenuates it.

Calmodulin (CaM): A Ca2+-binding regulatory protein that modulates the activity of Ca2+-sensitive adenylyl cyclase isoforms upon binding.

Forskolin: A small-molecule activator that binds directly to adenylyl cyclase catalytic domains, stabilising the active conformation.

References

1. Structural insights into membrane adenylyl cyclases, initiators of cAMP signaling. Trends in Biochemical Sciences (2023).
2. The membrane domains of mammalian adenylyl cyclases are lipid receptors. eLife (2024).
3. Regulatory sites of CaM-sensitive adenylyl cyclase AC8 revealed by cryo-EM and structural proteomics. EMBO Reports (2024).
4. Distinct patterns of bidirectional regulation of mammalian adenylyl cyclases.. Journal of Biological Chemistry (1994).
5. Regulation of Adenylyl Cyclase by Protein Kinase A *. Journal of Biological Chemistry (1995).