cAMP-dependent protein kinase (PKA) (PKA)

The cAMP-dependent protein kinase (PKA) is a central effector in the G protein-coupled receptor (GPCR) signaling cascade, specifically the Gs-alpha pathway [1, 11]. The PKA holoenzyme is a heterotetramer composed of two regulatory subunits that inhibit two catalytic subunits in the absence of cAMP [11, 12]. Upon activation of adenylyl cyclase and the subsequent rise in intracellular cyclic AMP (cAMP) levels, cAMP binds to the regulatory subunits, triggering the release of active catalytic subunits [11, 12]. These subunits then phosphorylate a wide array of target proteins, including transcription factors like CREB, metabolic enzymes, and ion channels, thereby regulating processes such as glucose metabolism, cell growth, and synaptic plasticity [4, 8]. Dysregulation of the PKA pathway is implicated in various pathologies, including endocrine tumors (e.g., Carney complex, Cushing syndrome), cardiovascular diseases, and neurodegenerative disorders [4, 11]. While direct PKA inhibitors are primarily used as research tools due to the enzyme's ubiquitous expression and potential for systemic toxicity, the pathway is frequently modulated therapeutically through upstream targets like GPCRs and phosphodiesterases (PDEs) [1, 5]. Targeting PKA directly remains a significant challenge in drug development because of its essential role in nearly every cell type, making it a classic anti-target for systemic therapy [9].

Other names

Protein kinase ACyclic AMP-dependent protein kinasecAMP-dependent protein kinase holoenzymecAMP-dependent protein kinase A

Drugs targeting the PKA pathway act by directly inhibiting the catalytic subunits, antagonizing the cAMP binding sites on regulatory subunits, or indirectly modulating cAMP levels via adenylyl cyclase activation or phosphodiesterase inhibition [1, 7, 8].