Protein Kinase A in neurological disorders

Abstract

Cyclic adenosine 3', 5' monophosphate (cAMP)-dependent Protein Kinase A (PKA) is a multi-functional serine/threonine kinase that regulates a wide variety of physiological processes including gene transcription, metabolism, and synaptic plasticity. Genomic sequencing studies have identified both germline and somatic variants of the catalytic and regulatory subunits of PKA in patients with metabolic and neurodevelopmental disorders. In this review we discuss the classical cAMP/PKA signaling pathway and the disease phenotypes that result from PKA variants. This review highlights distinct isoform-specific cognitive deficits that occur in both PKA catalytic and regulatory subunits, and how tissue-specific distribution of these isoforms may contribute to neurodevelopmental disorders in comparison to more generalized endocrine dysfunction.

Keywords: CREB; Cognition; Endocrine Systems; Gene transcription; Kinases; Learning; MAPK; Memory; Metabolic Disorders; Movement Disorders; Neurodegeneration; Neurodevelopment; PKA; Protein phosphorylation; cAMP.

Fig. 1

The Catalytic Subunit: A Representative AlphaFold Structure of the Cα1 catalytic subunit of PKA. The protein N-terminus (MGNAAAAKGSEQES) is highlighted in hot pink, and the more conserved regions of the catalytic subunit are colored in green. B Multiple sequence alignment of the N-terminus for the PKA catalytic subunit isoforms Cα1, Cα2, Cα3, Cβ1, Cγ, and Cχ

Fig. 2

The Regulatory Subunit: A Schematic representation of the structural domains encoded by the PKA regulatory subunits. B Two representations of the predicted AlphaFold structure of a PRKAR1B dimer. The DD domain is colored in magenta, the inhibitory segment is colored in grey, CNB-A in blue, and CNB-B in orange. The linker region between the two CNB’s is colored in black

Fig. 3

Common PKA signaling pathways: Diagram of the MAPK and PKA pathways. Signaling events leading to Elk1-mediated transcription are shown on the left, while those leading to CREB-mediated transcription are shown on the right. Depending on cell context, PKA either positively or negatively regulates Ras-MAPK signaling. Moreover, MAPK indirectly stimulates CREB-mediated transcription via activation of ribosomal protein S6 kinases (RSKs)