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Calcium release from the endoplasmic reticulum (ER) is predominantly driven by two key ion channel receptors, inositol 1, 4, 5‐triphosphate receptor (InsP3R) in non‐excitable cells and ryanodine receptor (RyR) in excitable and muscle‐based cells. These calcium transients can be modified by other less‐studied ion channels, including polycystin 2 (PC2), a member of the transient receptor potential (TRP) family. PC2 is found in various cell types and is evolutionarily conserved with paralogues ranging from single‐cell organisms to yeasts and mammals. Interest in the mammalian form of PC2 stems from its disease relevance, as mutations in the PKD2 gene, which encodes PC2, result in autosomal dominant polycystic kidney disease (ADPKD). This disease is characterized by renal and liver cysts, and cardiovascular extrarenal manifestations. However, in contrast to the well‐defined roles of many TRP channels, the role of PC2 remains unknown, as it has different subcellular locations, and the functional understanding of the channel in each location is still unclear. Recent structural and functional studies have shed light on this channel. Moreover, studies on cardiovascular tissues have demonstrated a diverse role of PC2 in these tissues compared to that in the kidney. We highlight recent advances in understanding the role of this channel in the cardiovascular system and discuss the functional relevance of PC2 in non‐renal cells. [ABSTRACT FROM AUTHOR]

The left‐right organizer (LRO) in the mouse consists of pit cells within the depression, located at the end of the developing notochord, also known as the embryonic node and crown cells lining the outer periphery of the node. Cilia on pit cells are posteriorly tilted, rotate clockwise and generate leftward fluid flow. Primary cilia on crown cells are required to interpret the directionality of fluid movement and initiate flow‐dependent gene transcription. Crown cells express PC1‐L1 and PC2, which may form a heteromeric polycystin channel complex on primary cilia. It is still only poorly understood how fluid flow activates the ciliary polycystin complex. Besides polycystin channels voltage gated channels like HCN4 and KCNQ1 have been implicated in establishing asymmetry. How this electrical network of ion channels initiates left‐sided signalling cascades and differential gene expression is currently only poorly defined. [ABSTRACT FROM AUTHOR]

Keywords: ADPKD; calcium signalling; cystogenesis; medicine; PKD2; polycystin; TACAN EN ADPKD calcium signalling cystogenesis medicine PKD2 polycystin TACAN 887 888 2 03/03/23 20230301 NES 230301 Introduction Mutations in I PKD1 i and I PKD2 i are the leading cause of autosomal dominant polycystic kidney disease (ADPKD). The study reported that TACAN physically interacts with PKD2, inhibits PKD2 channel activity and increases pronephric cysts in I PKD2 i -knockdown (KD) zebrafish. [Extracted from the article]

Key points: Significant and selective up‐regulation of the Na+/H+ exchanger NHA2 (SLC9B2) was observed in cysts of patients with autosomal dominant polycystic kidney disease.Using the MDCK cell model of cystogenesis, it was found that NHA2 increases cyst size. Silencing or pharmacological inhibition of NHA2 inhibits cyst formation in vitro.Polycystin‐1 represses NHA2 expression via Ca2+/NFAT signalling whereas the dominant negative membrane‐anchored C‐terminal fragment (PC1‐MAT) increased NHA2 levels.Drugs (caffeine, theophylline) and hormones (vasopressin, aldosterone) known to exacerbate cysts elicit NHA2 expression.Taken together, the findings reveal NHA2 as a potential new player in salt and water homeostasis in the kidney and in the pathogenesis of polycystic kidney disease. Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 and PKD2 encoding polycystin‐1 (PC1) and polycystin‐2 (PC2), respectively. The molecular pathways linking polycystins to cyst development in ADPKD are still unclear. Intracystic fluid secretion via ion transporters and channels plays a crucial role in cyst expansion in ADPKD. Unexpectedly, we observed significant and selective up‐regulation of NHA2, a member of the SLC9B family of Na+/H+ exchangers, that correlated with cyst size and disease severity in ADPKD patients. Using three‐dimensional cultures of MDCK cells to model cystogenesis in vitro, we showed that ectopic expression of NHA2 is causal to increased cyst size. Induction of PC1 in MDCK cells inhibited NHA2 expression with concordant inhibition of Ca2+ influx through store‐dependent and ‐independent pathways, whereas reciprocal activation of Ca2+ influx by the dominant negative membrane‐anchored C‐terminal tail fragment of PC1 elevated NHA2. We showed that NHA2 is a target of Ca2+/NFAT signalling and is transcriptionally induced by methylxanthine drugs such as caffeine and theophylline, which are contraindicated in ADPKD patients. Finally, we observed robust induction of NHA2 by vasopressin, which is physiologically consistent with increased levels of circulating vasopressin and up‐regulation of vasopressin V2 receptors in ADPKD. Our findings have mechanistic implications on the emerging use of vasopressin V2 receptor antagonists such as tolvaptan as safe and effective therapy for polycystic kidney disease and reveal a potential new regulator of transepithelial salt and water transport in the kidney. Key points: Significant and selective up‐regulation of the Na+/H+ exchanger NHA2 (SLC9B2) was observed in cysts of patients with autosomal dominant polycystic kidney disease.Using the MDCK cell model of cystogenesis, it was found that NHA2 increases cyst size. Silencing or pharmacological inhibition of NHA2 inhibits cyst formation in vitro.Polycystin‐1 represses NHA2 expression via Ca2+/NFAT signalling whereas the dominant negative membrane‐anchored C‐terminal fragment (PC1‐MAT) increased NHA2 levels.Drugs (caffeine, theophylline) and hormones (vasopressin, aldosterone) known to exacerbate cysts elicit NHA2 expression.Taken together, the findings reveal NHA2 as a potential new player in salt and water homeostasis in the kidney and in the pathogenesis of polycystic kidney disease. [ABSTRACT FROM AUTHOR]