The sperm-specific CatSper channel controls the intracellular Ca(2+) concentration ([Ca(2+)](i)) and, thereby, the swimming behaviour of sperm. In humans, CatSper is directly activated by progesterone and prostaglandins-female factors that stimulate Ca(2+) influx. Other factors including neurotransmitters, chemokines, and odorants also affect sperm function by changing [Ca(2+)](i). Several ligands, notably odorants, have been proposed to control Ca(2+) entry and motility via G protein-coupled receptors (GPCRs) and cAMP-signalling pathways. Here, we show that odorants directly activate CatSper without involving GPCRs and cAMP. Moreover, membrane-permeable analogues of cyclic nucleotides that have been frequently used to study cAMP-mediated Ca(2+) signalling also activate CatSper directly via an extracellular site. Thus, CatSper or associated protein(s) harbour promiscuous binding sites that can host various ligands. These results contest current concepts of Ca(2+) signalling by GPCR and cAMP in mammalian sperm: ligands thought to activate metabotropic pathways, in fact, act via a common ionotropic mechanism. We propose that the CatSper channel complex serves as a polymodal sensor for multiple chemical cues that assist sperm during their voyage across the female genital tract.

During antidiuresis, increases in vasopressin (AVP)-elicited osmotic water permeability in the terminal inner medullary collecting duct (tIMCD) raise luminal calcium concentrations to levels ( Ն 5 mM) above those associated with the formation of calcium-containing precipitates in the urine. Calcium/polycation receptor proteins (CaRs) enable cells in the parathyroid gland and kidney thick ascending limb of Henle to sense and respond to alterations in serum calcium. We now report the presence of an apical CaR in rat kidney tIMCD that specifically reduces AVP-elicited osmotic water permeability when luminal calcium rises. Purified tIMCD apical membrane endosomes contain both the AVP-elicited water channel, aquaporin 2, and a CaR. In addition, aquaporin 2-containing endosomes also possess stimulatory (G ␣ q / G ␣ 11 ) and inhibitory (G ␣ i1, 2, and 3 ) GTP binding proteins reported previously to interact with CaRs as well as two specific isoforms (delta and zeta) of protein kinase C.Immunocytochemistry using anti-CaR antiserum reveals the presence of CaR protein in both rat and human collecting ducts. Together, these data provide support for a unique tIMCD apical membrane signaling mechanism linking calcium and water metabolism. Abnormalities in this mechanism could potentially play a role in the pathogenesis of renal stone formation. ( J. Clin. Invest. 1997. 99:1399-1405.)

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Low-protein diets cause a urinary concentrating defect in rats and humans. Previously, we showed that feeding rats a low (8%) protein diet induces a change in urea transport in initial inner medullary collecting ducts (IMCDs) which could contribute to the concentrating defect. Now, we test whether decreased osmotic water permeability (P f ) contributes to the concentrating defect by measuring P f in perfused initial and terminal IMCDs from rats fed 18 or 8% protein for 2 wk. In terminal IMCDs, arginine vasopressin (AVP)-stimulated osmotic water permeability was significantly reduced in rats fed 8% protein compared to rats fed 18% protein.

Hedgehog (Hh) family members are involved in multiple cellular processes including proliferation, migration, differentiation, and cell fate determination. Recently, the novel Hh agonists Hh-Ag 1.3 and 1.7 were identified in a high-throughput screening of small molecule compounds that activate the expression of Gli1, a target of Hh signaling. This study demonstrates that Hh-Ag 1.3 and 1.7 strongly activate the expression of endogenous Gli1 and promote osteoblast differentiation in the mesenchymal stem cell line C3H10T1/2. Both compounds stimulated alkaline phosphatase activity in a dose-dependent manner, and induced osteoblast marker gene expression in C3H10T1/2 cells, which indicated that they had acquired an osteoblast identity. Of the markers, the expression of osterix/Sp7, a downstream target of runt-related transcription factor (Runx)2, was induced by Hh-Ag 1.7, which also rescued the osteoblast differentiation defect of RD-127, a mesenchymal cell line from Runx2-deficient mice. Hh-Ags also activated canonical Wnt signaling and synergized with low doses of BMP-2 to enhance osteoblastic potential. Thus, Hh-Ag 1.7 could be useful for bone healing in individuals with abnormalities in osteogenesis, such as osteoporosis patients and the elderly, and can contribute to the development of novel therapeutics for the treatment of bone fractures and defects.

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