Transient receptor potential (TRP) proteins form Ca²⁺-permeable, nonselective cation channels, but their role in neuronal Ca²⁺ homeostasis is elusive. In the present paper, we show that TRPC channels potently regulate synaptic plasticity by changing the presynaptic Ca²⁺-homeostasis of hippocampal neurons. Specifically, loss of TRPC1/C4/C5 channels decreases basal-evoked secretion, reduces the pool size of readily releasable vesicles, and accelerates synaptic depression during high-frequency stimulation (HFS). In contrast, primary TRPC5 channel-expressing neurons, identified by a novel TRPC5–τ-green fluorescent protein (τGFP) knockin mouse line, show strong short-term enhancement (STE) of synaptic signaling during HFS, indicating a key role of TRPC5 in short-term plasticity. Lentiviral expression of either TRPC1 or TRPC5 turns classic synaptic depression of wild-type neurons into STE, demonstrating that TRPCs are instrumental in regulating synaptic plasticity. Presynaptic Ca²⁺ imaging shows that TRPC activity strongly boosts synaptic Ca²⁺ dynamics, showing that TRPC channels provide an additional presynaptic Ca²⁺ entry pathway, which efficiently regulates synaptic strength and plasticity.

Plasma calcium (Ca ²⁺ ) is maintained by amending the release of parathyroid hormone and through direct effects of the Ca ²⁺ -sensing receptor (CaSR) in the renal tubule. Combined, these mechanisms alter intestinal Ca ²⁺ absorption by modulating 1,25-dihydroxyvitamin D ₃ production, bone resorption, and renal Ca ²⁺ excretion. The CaSR is a therapeutic target in the treatment of secondary hyperparathyroidism and hypocalcemia, a common complication of calcimimetic therapy. The CaSR is also expressed in intestinal epithelium; however, a direct role in regulating local intestinal Ca ²⁺ absorption is unknown. Chronic CaSR activation decreased expression of genes involved in Ca ²⁺ absorption. In Ussing chambers, increasing extracellular Ca ²⁺ or basolateral application of the calcimimetic cinacalcet decreased net Ca ²⁺ absorption across intestinal preparations acutely. Conversely, Ca ²⁺ absorption increased with decreasing extracellular Ca ²⁺ concentration. These responses were absent in mice expressing a nonfunctional TRPV6, TRPV6 ^D541A . Cinacalcet also attenuated Ca ²⁺ fluxes through TRPV6 in Xenopus oocytes when coexpressed with the CaSR. Moreover, the phospholipase C inhibitor U73122 prevented cinacalcet-mediated inhibition of Ca ²⁺ flux. These results reveal a regulatory pathway whereby activation of the CaSR in the basolateral membrane of the intestine directly attenuates local Ca ²⁺ absorption via TRPV6 to prevent hypercalcemia and help explain how calcimimetics induce hypocalcemia.

Regulated exocytosis is initiated by increased Ca ²⁺ concentrations in close spatial proximity to secretory granules, which is effectively prevented when the cell is at rest. Here we showed that exocytosis of zymogen granules in acinar cells was driven by Ca ²⁺ directly released from acidic Ca ²⁺ stores including secretory granules through NAADP-activated two-pore channels (TPCs). We identified OCaR1 (encoded by Tmem63a ) as an organellar Ca ²⁺ regulator protein integral to the membrane of secretory granules that controlled Ca ²⁺ release via inhibition of TPC1 and TPC2 currents. Deletion of OCaR1 led to extensive Ca ²⁺ release from NAADP-responsive granules under basal conditions as well as upon stimulation of GPCR receptors. Moreover, OCaR1 deletion exacerbated the disease phenotype in murine models of severe and chronic pancreatitis. Our findings showed OCaR1 as a gatekeeper of Ca ²⁺ release that endows NAADP-sensitive secretory granules with an autoregulatory mechanism preventing uncontrolled exocytosis and pancreatic tissue damage.

Calcium-selective transient receptor potential Vanilloid 6 (TRPV6) channels are expressed in fetal labyrinth trophoblasts as part of the feto–maternal barrier, necessary for sufficient calcium supply, embryo growth, and bone development during pregnancy. Recently, we have shown a less- compact labyrinth morphology of Trpv6-deficient placentae, and reduced Ca²⁺ uptake of primary trophoblasts upon functional deletion of TRPV6. Trpv6^-/- trophoblasts show a distinct calcium-dependent phenotype. Deep proteomic profiling of wt and Trpv6^-/- primary trophoblasts using label-free quantitative mass spectrometry leads to the identification of 2778 proteins. Among those, a group of proteases, including high-temperature requirement A serine peptidase 1 (HTRA1) and different granzymes are more abundantly expressed in Trpv6^-/- trophoblast lysates, whereas the extracellular matrix protein fibronectin and the fibronectin-domain-containing protein 3A (FND3A) were markedly reduced. Trpv6^-/-placenta lysates contain a higher intrinsic proteolytic activity increasing fibronectin degradation. Our results show that the extracellular matrix formation of the placental labyrinth depends on TRPV6; its deletion in trophoblasts correlates with the increased expression of proteases controlling the extracellular matrix in the labyrinth during pregnancy.