TRPV4 is the temperature-sensitive ion channel of human sperm.

Ion channels control the ability of human sperm to fertilize the egg by triggering hyperactivated motility, which is regulated by membrane potential, intracellular pH, and cytosolic calcium. Previous studies unraveled three essential ion channels that regulate these parameters: (1) the Ca2+ channel CatSper, (2) the K+ channel KSper, and (3) the H+ channel Hv1. However, the molecular identity of the sperm Na+ conductance that mediates initial membrane depolarization and, thus, triggers downstream signaling events is yet to be defined. Here, we functionally characterize DSper, the Depolarizing Channel of Sperm, as the temperature-activated channel TRPV4. It is functionally expressed at both mRNA and protein levels, while other temperature-sensitive TRPV channels are not functional in human sperm. DSper currents are activated by warm temperatures and mediate cation conductance, that shares a pharmacological profile reminiscent of TRPV4. Together, these results suggest that TRPV4 activation triggers initial membrane depolarization, facilitating both CatSper and Hv1 gating and, consequently, sperm hyperactivation

Cilia-enriched oxysterol 7β,27-DHC is required for polycystin ion channel activation.

Polycystin-1 (PC-1) and PC-2 form a heteromeric ion channel complex that is abundantly expressed in primary cilia of renal epithelial cells. This complex functions as a non-selective cation channel, and mutations within the polycystin complex cause autosomal dominant polycystic kidney disease (ADPKD). The spatial and temporal regulation of the polycystin complex within the ciliary membrane remains poorly understood. Using both whole-cell and ciliary patch-clamp recordings, we identify a cilia-enriched oxysterol, 7β,27-dihydroxycholesterol (DHC), that serves as a necessary activator of the polycystin complex. We further identify an oxysterol-binding pocket within PC-2 and showed that mutations within this binding pocket disrupt 7β,27-DHC-dependent polycystin activation. Pharmacologic and genetic inhibition of oxysterol synthesis reduces channel activity in primary cilia. In summary, our findings reveal a regulator of the polycystin complex. This oxysterol-binding pocket in PC-2 may provide a specific target for potential ADPKD therapeutics

TRPV4 is the temperature-sensitive ion channel of human sperm

Ion channels control the ability of human sperm to fertilize the egg by triggering hyperactivated motility, which is regulated by membrane potential, intracellular pH, and cytosolic calcium. Previous studies unraveled three essential ion channels that regulate these parameters: (1) the Ca2+ channel CatSper, (2) the K+ channel KSper, and (3) the H+ channel Hv1. However, the molecular identity of the sperm Na+ conductance that mediates initial membrane depolarization and, thus, triggers downstream signaling events is yet to be defined. Here, we functionally characterize DSper, the Depolarizing Channel of Sperm, as the temperature-activated channel TRPV4. It is functionally expressed at both mRNA and protein levels, while other temperature-sensitive TRPV channels are not functional in human sperm. DSper currents are activated by warm temperatures and mediate cation conductance, that shares a pharmacological profile reminiscent of TRPV4. Together, these results suggest that TRPV4 activation triggers initial membrane depolarization, facilitating both CatSper and Hv1 gating and, consequently, sperm hyperactivation

Stabilizing mandibular complete dentures by a single midline implant-influence on quality of life: 2-year results from a randomized clinical trial comparing different loading protocols.

OBJECTIVES The knowledge about the influence of dental treatment on health-related quality of life (HRQoL) is still limited. The aim of this multicenter randomized controlled clinical trial was to assess the effect of stabilizing an existing complete denture, by means of a single mandibular implant, on HRQoL. Furthermore, the impact of the loading protocol, i.e., immediate or delayed loading, in edentulous patients was evaluated. METHODS One hundred fifty-eight participants aged 60-89 years were randomly assigned to study group A (immediate loading; n = 81) and to group B (delayed loading; n = 78). All participants received a single midline implant in the mandible. The implants were either immediately loaded (group A) or after a closed healing period of 3 months (group B) by connecting the existing mandibular complete dentures to ball attachments. HRQoL was assessed with the Short Form-36 questionnaire of health (SF-36) at baseline, 4 months, and 24 months after implant loading. RESULTS Improvement of HRQoL by means of a single implant-retained mandibular overdenture could not be demonstrated after 4 and 24 months of implant loading. Furthermore, the application of two different loading protocols did not influence HRQoL ratings of study participants. CONCLUSION The loading protocol is not a factor, influencing HRQoL in patients treated by a single midline implant in the edentulous mandible. CLINICAL RELEVANCE A single midline implant in the edentulous mandible, stabilizing a mandibular complete denture, cannot be recommended for improving HRQoL