Polycystin-1 (PC1) (PC1)

Polycystin-1 (PC1) is a large, multi-pass transmembrane protein encoded by the PKD1 gene, primarily localized to the primary cilia and plasma membrane of renal epithelial cells (UniProt P98161). It functions as a mechanosensor and a non-canonical G protein-coupled receptor that forms a functional complex with Polycystin-2 to regulate intracellular calcium levels and maintain normal tubular morphology (PubMed: 28238418). Mutations in PKD1, which account for approximately 85% of Autosomal Dominant Polycystic Kidney Disease (ADPKD) cases, lead to the production of variant PC1 proteins that are either non-functional, unstable, or improperly trafficked (PubMed: 30630771). This dysfunction triggers aberrant signaling pathways, including increased cAMP and mTOR activity, resulting in uncontrolled cell proliferation and fluid-filled cyst formation. The severity of the disease is often linked to the specific type of PKD1 mutation, with truncating variants typically leading to more aggressive cyst growth than non-truncating missense variants (PubMed: 25538273). While current pharmacological interventions like Tolvaptan target downstream signaling to slow disease progression, emerging research focuses on direct modulation of variant PC1 through chemical chaperones or gene-based therapies to restore protein function (PubMed: 31534025). As a critical regulator of renal homeostasis, PC1 represents a central node in the pathophysiology of cystic kidney diseases and a primary focus for precision medicine approaches.

Other names

Polycystic kidney disease 1 proteinPKD1TRPP1Transient receptor potential polycystic 1

Antagonism of the vasopressin V2 receptor to lower cAMP, inhibition of somatostatin receptors to reduce fluid secretion, and modulation of downstream kinase pathways (mTOR, EGFR) to suppress cyst growth and compensate for PC1 loss of function.