Abstract
Transient receptor potential channels-vanilloid receptor 1 (TRPV1) regulates thermotaxis in sperm-oriented motility. We investigated the role of membrane cholesterol (Chol) on TRPV1-mediated human sperm migration. Semen samples were obtained from five normozoospemic healthy volunteers. Sperm membrane Chol content, quantified by liquid chromatography-mass spectrometry, was modified by incubating cells with 2-hydroxypropyl-ß-cyclodextrin (CD) or the complex between CD and Chol (CD:Chol). The effect on sperm migration on a 10 μM capsaicin gradient (CPS), a TRPV1 agonist, was then investigated. Motility parameters were evaluated by Sperm Class Analyser. Intracellular calcium concentration and acrosome reaction were measured by staining with calcium orange and FITC-conjugated anti-CD46 antibody, respectively. TRPV1-Chol interaction was modelled by computational molecular-modelling (MM). CD and CD:Chol, respectively, reduced and increased membrane Chol content in a dose-dependent manner, resulting in a dose-dependent increase and reduction of sperm migration in a CPS gradient. MM confirmed a specific interaction of Chol with a TRPV1 domain that appeared precluded to the Chol epimer epicholesterol (Epi-Chol). Accordingly, CD:Epi-Chol was significantly less efficient than CD:Chol, in reducing sperm migration under CPS gradient. Chol inhibits TRPV1-mediated sperm function by directly interacting with a consensus sequence of the receptor.
Highlights
The gain of sperm-oriented motility of sperm cells within the female reproductive tract is a key event contributing to the fertility potential [1]
The rate of the acrosome reaction was mainly unaffected by the migration towards the CPS gradient after the incubation with CD:Chol (Figure 2F). These results suggest that the membrane Chol content acts as a fine tuner of the Transient receptor potential channels-vanilloid receptor 1 (TRPV1)-mediated sperm migration
No obvious difference was detectable for the two sterols delivered at matched concentration (Figure 4E). These results suggest that the influence of membrane Chol on TRPV1mediated sperm migration is the likely result of the major specific interaction of the sterol with a corresponding TRPV1-binding domain, rather than a nonspecific influence on the overall membrane’s biophysical properties
Summary
The gain of sperm-oriented motility of sperm cells within the female reproductive tract is a key event contributing to the fertility potential [1]. At least three main mechanisms have been recognized to drive sperm cells through the female reproductive tract. The first is the oriented swimming of the sperm cell against the genital fluid flow, known as rheotaxis [2]. Chemotaxis drives the directional changes of the sperm movement towards the source of a chemoattractant source, such as progesterone, according to its concentration gradient [3,4]. The most studied long-range drive for spermatozoa is thermotaxis, allowing the cell to move according to a temperature gradient from the cooler site of sperm deposition to the warmer site of possible oocyte fertilization [5]. A redundancy of thermoreceptors has been acknowledged in the regulation of thermotaxis, 4.0/)
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