Polycystin-1, 2, and STIM1 Interact with IP₃R to Modulate ER Ca²⁺ Release through the PI3K/Akt Pathway

Abstract

Dysregulation of Ca²⁺ signaling and homeostasis has been linked to the development of ADPKD through aberrant functioning of the polycystins. In this study, we investigated the role of the polycystins in modulating Ca²⁺ signaling. Expression of full-length PC1 in MDCK cells inhibited intracellular Ca²⁺ release in response to ATP when compared to control cells. This phenotype correlated with reduced interaction of endogenous PC2 and IP₃R in PC1-containing cells. We also found that endogenous STIM1 also interacted with the IP₃R, and this interaction was enhanced by PC1 expression. Increased interaction between STIM1 and IP₃R inhibited Ca²⁺ release. PC1 regulates intracellular Ca²⁺ release and the interaction of PC2-IP₃R-STIM1 through the PI3K/Akt signaling pathway. Inhibition of the PI3K/Akt pathway in PC1 containing cells restored intracellular Ca²⁺ release, increased the interaction between PC2 and IP₃R and disrupted the STIM1-IP₃R complex. Conversely, activation of the PI3K/Akt signaling pathway by HGF in control MDCK cells gave the reverse effects. It reduced the release of Ca²⁺ to levels comparable to the PC1 cells, inhibited the association PC2 and IP₃R, and increased the interaction between STIM and IP₃R. Overall, our studies provide a potential mechanism for the modulation of intracellular Ca²⁺ signaling by the polycystins.

Tmem178 acts in a novel negative feedback loop targeting NFATc1 to regulate bone mass

“…In addition to associating with Orai1 to control SOCE, Stim1 also couples to numerous other Ca 2+ channels, Ca 2+ pumps, ER chaperone proteins, and regulatory adaptor proteins, thereby influencing multiple pathways of Ca 2+ transport (31). In kidney epithelial cells, Stim1 interacts with polycystin-1, diminishing IP3R-mediated ER Ca 2+ release (32). In aortic endothelial cells, Stim1 potentiates IP3R-mediated ER Ca 2+ release (33).…”

Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

“…[6][7][8] Polycystin-1 interacts with the inositol 1,4,5-trisphosphate receptor (IP3R). 9,10 Polycystin-2 is a transient receptor potential (TRP) channel that is mainly located in the endoplasmic reticulum, where it functions as a calcium release channel, and, possibly, located in the plasma membrane. 11,12 Polycystin-1 and fibrocystin interact with, and modulate the function of, polycystin-2.…”

“…22 For example, experiments in which polycystin-1 is knocked down conclude that polycystin-1 amplifies IP3-induced calcium release, 23 whereas studies using heterologous overexpression of polycystin-1 reach the opposite conclusion. 9,10 Nevertheless, most studies that have measured resting intracellular calcium, endoplasmic reticulum calcium stores, and store-operated calcium entry in primary cell cultures or microdissected samples from human and rodent polycystic tissues have found them to be reduced (Table 1). 17,[23][24][25][26][27][28][29][30][31] cholangiocytes, 37 vascular smooth muscle cells, 38 and choroid plexus.…”

Role of calcium in polycystic kidney disease: From signaling to pathology

“…In HEK293 cells, these calcium oscillations can be increased by either reduced or undetectable levels of PC1, but are only induced by the absence of PC2 ( Figure 2A). Normal calcium oscillations can be restored in PKD1-deficient cells via the reintroduction of mouse wild-type PC1, and in PKD2 knockout cells via the IP3R, and reduces the association between PC2 and the IP3 receptor [15] . Moreover, PC1 seems able to regulate intracellular calcium release and PC2-IP3R-STIM1 interaction through the PI3K/Akt signaling pathway [15] .…”

“…Indeed, PC1 and PC2 co-assembly has been seen to generate a cation-permeable current through the plasma membrane [11] , and PC1 and PC2 are known to regulate intracellular calcium release in the ER through their interaction with the inositol 1,4,5-trisphosphate receptor (IP3R) [12][13][14] . In this context, PC2 enhances calcium release from the ER by stimulating the activity of the IP3 receptor, while PC1 inhibits this process by reducing PC2-IP3R interaction via a mechanism involving the stromal interaction molecule-1 (STIM1) and the PI3K/Akt pathway [12,15] . PC1 can also regulate other types of calcium channels, including non-capacitative calcium entry (NCCE) channels, which are able to generate intracellular calcium oscillations [16] .…”