The molecular geography of cell signaling diseases.

Abstract

Precision pharmacology has emerged from advances in cell biology, microscopy, and signal transduction, revealing that intracellular communication is highly organized within spatially restricted compartments. Hence, therapeutic approaches that manage disease-associated signaling steps within defined subcellular microdomains are attractive precision pharmacology targets. A-kinase anchoring proteins coordinate this remarkable level of spatial organization by clustering protein kinase A with phosphatases and cAMP effector proteins. These signaling islands direct second messenger responses toward selected substrates while restricting inappropriate crosstalk. Perturbation of A-kinase anchoring protein-directed signaling contributes to cardiovascular disease, endocrine dysfunction, cancer progression, chronic pain, and neurodegeneration. Agents that selectively modulate or dismantle pathological signaling complexes may offer a less invasive means to therapeutically exploit the molecular geography of diseased cells, particularly if used in combination with molecular glues, chimera-targeted protein degradation targeted protein degradation, and selective kinase inhibitors. This article is a foreword for a series of 4 minireviews commissioned by the journal from speakers at the 2025 ASPET Axelrod Symposium on spatial cAMP signaling. These contributions examine how pathological perturbations in A-kinase anchoring protein-mediated signaling networks contribute to a diverse spectrum of disease processes, including maladaptive cardiac remodeling, endocrine hyperfunction, nociceptor sensitization, and synaptic failure in AD. SIGNIFICANCE STATEMENT: Intracellular signaling is a fundamental process that governs cellular physiology and disease pathogenesis. This miniseries highlights how A-kinase anchoring proteins assemble signaling nanodomains to locally control second messenger-responsive enzymes in the cardiovascular, endocrine, and nervous systems. A-kinase anchoring protein macromolecular assemblies are emerging venues for precision pharmacology.