Ciliary G-Protein Coupled Receptor Signaling in Polycystic Kidney Disease

Polycystic kidney disease (PKD), a ciliopathy caused primarily by mutations in the Pkd1 and Pkd2 genes, disrupts renal structure and function, leading to progressive renal failure. The primary cilium, a sensory organelle essential for cellular signaling, plays a pivotal role in maintaining renal function. Among its signaling components, G-protein-coupled receptors (GPCRs) within the cilium have gained significant attention for their localized functions and their contribution to PKD pathogenesis. Dysfunction of ciliary GPCR signaling alters key downstream pathways, including mammalian target of rapamycin (mTOR), cyclic adenosine monophosphate (cAMP), and calcium homeostasis, exacerbating cyst formation and disease progression. Additionally, interactions between ciliary GPCRs and PKD-associated proteins, such as Polycystin-1 (PC1) and Polycystin-2 (PC2), underline the complexity of PKD mechanisms. Recent advances highlight GPCRs as promising therapeutic targets for ciliopathies, including PKD. Emerging GPCR modulators and drugs in clinical trials show the potential to restore ciliary signaling and attenuate disease progression. This paper explores the physiological functions of ciliary GPCRs, their mechanistic links to PKD, and the therapeutic implications of targeting these receptors, offering insights into future research directions and therapeutic strategies for PKD.