Role and Modulation of TRPV1 in Mammalian Spermatozoa: An Updated Review

Abstract

Based on the abundance of scientific publications, the polymodal sensor TRPV1 is known as one of the most studied proteins within the TRP channel family. This receptor has been found in numerous cell types from different species as well as in spermatozoa. The present review is focused on analyzing the role played by this important channel in the post-ejaculatory life of spermatozoa, where it has been described to be involved in events such as capacitation, acrosome reaction, calcium trafficking, sperm migration, and fertilization. By performing an exhaustive bibliographic search, this review gathers, for the first time, all the modulators of the TRPV1 function that, to our knowledge, were described to date in different species and cell types. Moreover, all those modulators with a relationship with the reproductive process, either found in the female tract, seminal plasma, or spermatozoa, are presented here. Since the sperm migration through the female reproductive tract is one of the most intriguing and less understood events of the fertilization process, in the present work, chemotaxis, thermotaxis, and rheotaxis guiding mechanisms and their relationship with TRPV1 receptor are deeply analyzed, hypothesizing its (in)direct participation during the sperm migration. Last, TRPV1 is presented as a pharmacological target, with a special focus on humans and some pathologies in mammals strictly related to the male reproductive system.

Keywords: TRPV1; chemotaxis; endocannabinoid system; human; ion channel; mammals; sperm signaling; spermatozoa; thermotaxis.

Figure 1

Human TRPV channel subfamily dendrogram. The schema shows a graphical phylogenetic reconstruction of the TRPV subfamily, created from the alignment and phylogenetic reconstruction obtained after using ClustalW.

Figure 2

Structure of the TRPV1 channel. The image shows a simplified schema of the protein structure within the plasma membrane, consisting of six transmembrane helices (S1 to S6), a hydrophobic pore loop (PL) between S5 and S6, the N-terminal domain rich in ankyrin repeats and the C-terminal domain.

Figure 3

Three-dimensional structure of TRPV1. The image shows a caption of the protein structure obtained by Liao et coll. (2013) using single-particle electron cryo-microscopy [26]. Obtained from https://www.rcsb.org/structure/3J5P (accessed on 20 April 2021), PDB ID 3J5P [29,30].

Figure 4

Modulators of TRPV1 function. The schema shows most of the activators and modulators of TRPV1 function investigated to date, divided into two main groups: physical and physical stimuli; and chemical activators. Physical and mechanical modulators include temperature variations (heat or cold) [34], UV radiation [35,36], and mechanical stimuli [37]. The chemical activators group is divided in turn into two subgroups depending on the origin of the activator/modulator: exogenous and endogenous. Exogenous stimuli are capsaicin [38] and its antagonist capsazepine [39], resiniferatoxin (RTX) [37,40], bradykinin [41], yohimbine [42], ethanol [43], evodiamine [44], 17-β-estradiol [45], quinazoline [46], progesterone [47], numerous opioids [48], nicotine [49], hyaluronan [50], insulin [51], tinyatoxin [52], olvanil [53], acetylsalicylic acid [54], eugenol [55], sesquiterpenes [56,57,58], cannabidiol [59], prenylphenols [60], zingerone [61], shogaol [61], PPAHV [62], gingerol [63], numerous pharmacological antagonists [64,65,66,67], and peptide toxins from different species [4,68]. Endogenous activators comprise numerous compounds [1], such as the wide family derived from polyunsaturated fatty acids (PUFAs). According to the position of the first double bond present in their structures, this big family can be divided into n-3 (α-linolenic acid (ALA) and its products eicosapentanoic acid (EPA), docosahexaenoic acid (DHA), 20-hydroxyeicosapentaenoic acid (20-HEPE) and 22-hydroxyeicosapentaenoic acid (22-HDoHE)), and n-6 linoleic acid (LA) and its products γ-linoleic acid, arachidonic acid (AA) [69] (which produces hepoxylin, HXA-3, 14,15-epoxyeicosatrienoic acid, 14,15-EET, and 20-hydroxyeicosatetranoic acid, 20-HETE), 9- and 13-hydroxyoctadecadienoic acids (9-HODE and 13-HODE). Other agonists endogenously secreted are oxytocin [70], adenosine [71], nitric oxide [72], hydrogen sulfide (H₂S) [73], lysophosphatidic acid (LPA) [74] and its derivative diacylglycerol [75], pH variations [76,77], vitamin D [78], N-acyl amino acids/neurotransmitters [79], miRNAs [80,81], prostaglandins, nerve growth factors and the endocannabinoids family, including N-Acyl amides [82] (N-acyl GABAS [83,84] derived then in D-GABAs, L-GABA and A-GABA) and N-acylethanolamines (NAEs) [85], such as anandamide (AEA) *** [86], oleylethanolamine (OEA) [87] and palmitoylethanolamine (PEA) [88]. * Product from arachidonic acid. ** Derived also from oleic acid, identified as a TRPV1 natural inhibitor [89]. *** Can be exogenous and endogenous. Compounds evidenced in yellow have been found to produce an effect also in spermatozoa, being synthesized by them or present in the oviductal fluid or female reproductive tract.

Figure 5

Female oviduct and sperm migration. The diagram shows the female tract of mammals and the three sperm guidance mechanisms, depending on the site in which they have been described to act. While rheotaxis and thermotaxis have been suggested to act mostly in long-range distances, chemotaxis is supposed to take place only in the proximity of the female egg (considering that the exact fertilization site is species-dependent). The colors represent the thermal and chemical gradient (from left to right).