Impairment of TRPC1–STIM1 channel assembly and AQP5 translocation compromise agonist-stimulated fluid secretion in mice lacking caveolin1

Abstract

SummaryNeurotransmitter regulation of salivary fluid secretion is mediated by activation of Ca 2+ influx. The Ca 2+ -permeable transient receptor potential canonical 1 (TRPC1) channel is crucial for fluid secretion. However, the mechanism(s) involved in channel assembly and regulation are not completely understood. We report that Caveolin1 (Cav1) is essential for the assembly of functional TRPC1 channels in salivary glands (SG) in vivo and thus regulates fluid secretion. In Cav1 2/2 mouse SG, agonist-stimulated Ca 2+ entry and fluid secretion are significantly reduced. Microdomain localization of TRPC1 and interaction with its regulatory protein, STIM1, are disrupted in Cav1 2/2 SG acinar cells, whereas Orai1-STIM1 interaction is not affected. Furthermore, localization of aquaporin 5 (AQP5), but not that of inositol (1,4,5)-trisphosphate receptor 3 or Ca 2+ -activated K + channel (IK) in the apical region of acinar cell was altered in Cav1 2/2 SG. In addition, agonist-stimulated increase in surface expression of AQP5 required Ca 2+ influx via TRPC1 channels and was inhibited in Cav1 2/2 SG. Importantly, adenovirus-mediated expression of Cav1 in Cav1 2/2 SG restored interaction of STIM1 with TRPC1 and channel activation, apical targeting and regulated trafficking of AQP5, and neurotransmitter stimulated fluid-secretion. Together these findings demonstrate that, by directing cellular localization of TRPC1 and AQP5 channels and by selectively regulating the functional assembly TRPC1-STIM1 channels, Cav1 is a crucial determinant of SG fluid secretion.

Peroxisome Proliferator–Activated Receptor γ–Mediated Inhibition on Hypoxia-Triggered Store-Operated Calcium Entry. A Caveolin-1–Dependent Mechanism

“…Caveolin-1 can contribute to assembly of store-operated Ca 21 influx channels by regulating plasma membrane localization of TRPC1 in the caveolae compartment (41)(42)(43). Recent studies have further indicated that caveolin-1 not only directly interacts with TRPC1 (44,45), but also participates in the membrane localization and the cluster interaction of the main SOCC molecules, TRPC stromal interaction molecule (STIM)-ORAI calcium release activated calcium modulator (ORAI), upon intracellular calcium store depletion and the intracellular calcium sensor stromal interaction molecule 1 (STIM1) translocation, which is believed to be a key event during intracellular calcium mobilization (46).…”

Activation of muscarinic receptors in rat parotid acinar cells induces AQP5 trafficking to nuclei and apical plasma membrane

“…AQP5 is known to be present in parotid gland exosomes [13,14], which accumulate within multivesicular bodies and are released into saliva from parotid cells upon fusion of multivesicular bodies with the plasma membrane in a Ca 2+ -triggered reaction [15,16]. In salivary glands, the Ca 2+ -permeable transient receptor potential canonical 1 (TRPC1) plays an important role in the agonist-induced increase in [Ca 2+ ]i [2,17]. AQP5 was also demonstrated to be rapidly translocated from the cytoplasm to the APM by enhancement of [Ca 2+ ]i during sweating in sweat glands [18].…”

STIM1 and STIM2 Proteins Differently Regulate Endogenous Store-operated Channels in HEK293 Cells

“…The CRAC-activating domain of STIM1 is necessary for the interaction with TRPC, whereas its C-terminal cationic lysine-rich region is necessary for TRPC activation (50 -53). This TRPC-STIM1 cooperation plays a role in physiological functions such as fluid secretion in salivary glands (54), postnatal differentiation of human myoblasts (36), and disruption of the endothelial barrier (35). STIM2 protein has been less studied than STIM1.…”