Cyclic Nucleotide Signaling and Therapeutic Applications

Cyclic nucleotides, notably cyclic adenosine-3′,5′-monophosphate (cAMP) and cyclic guanosine-3′,5′-monophosphate (cGMP), serve as ubiquitous intracellular second messengers that convert extracellular cues into precise physiological responses. Synthesised by adenylyl and guanylyl cyclases and degraded by cyclic nucleotide phosphodiesterases (PDEs), these molecules regulate diverse processes including cardiac contractility, neuronal plasticity, vascular tone, immune cell function and renal homeostasis. Signal specificity is achieved through spatial and temporal compartmentalisation within subcellular nanodomains, often orchestrated by anchoring proteins that localise protein kinase A (PKA) or exchange proteins directly activated by cAMP (EPAC). Therapeutic strategies targeting cyclic nucleotide pathways encompass selective PDE inhibitors, cyclase modulators and receptor agonists, yielding approved treatments for cardiovascular disease, pulmonary hypertension, inflammatory disorders and erectile dysfunction. Emerging approaches aim to refine subcellular targeting and exploit repurposed agents for oncological and immune-modulatory applications.

Research from Nature Portfolio

Recent studies have revealed that neuronal endoplasmic reticulum–plasma membrane junctions host dedicated PKA signalosomes, enabling membrane depolarisation and calcium entry to drive excitation-transcription coupling independently of classical receptor activation. This discovery underscores a receptor-independent axis of cyclic nucleotide signalling that translates electrical stimuli into gene regulatory programmes within nanometre-scale domains. Complementing this, advanced fluorescence resonance energy transfer sensors have delineated local cAMP microdomains at cardiac β-adrenergic targets, demonstrating that discrete cAMP kinetics at plasmalemmal, sarcoplasmic and myofilament sites are essential for fine-tuning contractile function under both physiological and pathological conditions. These insights illuminate the molecular architecture of compartmentalised cyclic nucleotide signalling and suggest avenues for precision modulation of PKA-dependent processes.

Cyclic Nucleotide Signaling and Therapeutic Applications publication trend

The graph below shows the total number of articles in cyclic nucleotide signaling and therapeutic applications across all publications each year (not limited to Nature Index journals).

Technical terms

cAMP: Cyclic adenosine-3′,5′-monophosphate, a second messenger synthesised by adenylyl cyclase and degraded by PDEs to regulate PKA and EPAC pathways.

cGMP: Cyclic guanosine-3′,5′-monophosphate, a second messenger produced by guanylyl cyclase, involved in vasodilation and phototransduction.

PDEs: Cyclic nucleotide phosphodiesterases, enzyme families that hydrolyse cAMP and cGMP to terminate signalling.

PKA: Protein kinase A, a serine/threonine kinase activated by cAMP that phosphorylates numerous effectors.

EPAC: Exchange protein directly activated by cAMP, a guanine nucleotide exchange factor influencing Rap GTPases.

Nanodomain: Subcellular compartment, often <100 nm, where signalling components are concentrated for localised responses.

Signalosome: Multiprotein complex organising cyclic nucleotide synthesis, degradation and effector engagement at specific sites.

β-Adrenergic stimulation: Activation of β-adrenergic receptors by catecholamines, leading to cyclase activation and cAMP generation.

References

1. Cyclic nucleotide phosphodiesterases as drug targets. Pharmacological Reviews (2025).
2. Neuronal ER-plasma membrane junctions couple excitation to Ca2+-activated PKA signaling. Nature Communications (2023).
3. FRET biosensor uncovers cAMP nano-domains at β-adrenergic targets that dictate precise tuning of cardiac contractility. Nature Communications (2017).
4. PDE5 inhibitors against cancer via mediating immune cells in tumor microenvironment: AI‐based approach for future drug repurposing exploration. Interdisciplinary Medicine (2024).
5. Whole-heart multiparametric optical imaging reveals sex-dependent heterogeneity in cAMP signaling and repolarization kinetics. Science Advances (2023).