The transient receptor potential (TRP) superfamily consists of a large number of cation channels that are mostly permeable to both monovalent and divalent cations. The 28 mammalian TRP channels can be subdivided into six main subfamilies: the TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), and the TRPA (ankyrin) groups. TRP channels are expressed in almost every tissue and cell type and play an important role in the regulation of various cell functions. Currently, significant scientific effort is being devoted to understanding the physiology of TRP channels and their relationship to human diseases. At this point, only a few channelopathies in which defects in TRP genes are the direct cause of cellular dysfunction have been identified. In addition, mapping of TRP genes to susceptible chromosome regions (e.g., translocations, breakpoint intervals, increased frequency of polymorphisms) has been considered suggestive of the involvement of these channels in hereditary diseases. Moreover, strong indications of the involvement of TRP channels in several diseases come from correlations between levels of channel expression and disease symptoms. Finally, TRP channels are involved in some systemic diseases due to their role as targets for irritants, inflammation products, and xenobiotic toxins. The analysis of transgenic models allows further extrapolations of TRP channel deficiency to human physiology and disease. In this review, we provide an overview of the impact of TRP channels on the pathogenesis of several diseases and identify several TRPs for which a causal pathogenic role might be anticipated.

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Transient Receptor Potential Cation Channels in Disease

The transient receptor potential (TRP) protein superfamily consists of a diverse group of cation channels that bear structural similarities to Drosophila TRP. TRP channels play important roles in nonexcitable cells; however, an emerging theme is that many TRP-related proteins are expressed predominantly in the nervous system and function in sensory physiology. The TRP superfamily is divided into seven subfamilies, the first of which is composed of the "classical" TRPs" (TRPC subfamily). Some TRPCs may be store-operated channels, whereas others appear to be activated by production of diacylglycerol or regulated through an exocytotic mechanism. Many members of a second subfamily (TRPV) function in sensory physiology and respond to heat, changes in osmolarity, odorants, and mechanical stimuli. Two members of the TRPM family function in sensory perception and three TRPM proteins are chanzymes, which contain C-terminal enzyme domains. The fourth and fifth subfamilies, TRPN and TRPA, include proteins with many ankyrin repeats. TRPN proteins function in mechanotransduction, whereas TRPA1 is activated by noxious cold and is also required for the auditory response. In addition to these five closely related TRP subfamilies, which comprise the Group 1 TRPs, members of the two Group 2 TRP subfamilies, TRPP and TRPML, are distantly related to the group 1 TRPs. Mutations in the founding members of these latter subfamilies are responsible for human diseases. Each of the TRP subfamilies are represented by members in worms and flies, providing the potential for using genetic approaches to characterize the normal functions and activation mechanisms of these channels.

The TRP Superfamily of Cation Channels

Calcium and cyclic nucleotides have crucial roles in mammalian fertilization, but the molecules comprising the Ca2+-permeation pathway in sperm motility are poorly understood. Here we describe a putative sperm cation channel, CatSper, whose amino-acid sequence most closely resembles a single, six-transmembrane-spanning repeat of the voltage-dependent Ca2+-channel four-repeat structure. CatSper is located specifically in the principal piece of the sperm tail. Targeted disruption of the gene results in male sterility in otherwise normal mice. Sperm motility is decreased markedly in CatSper-/- mice, and CatSper-/- sperm are unable to fertilize intact eggs. In addition, the cyclic-AMP-induced Ca2+ influx is abolished in the sperm of mutant mice. CatSper is thus vital to cAMP-mediated Ca2+ influx in sperm, sperm motility and fertilization. CatSper represents an excellent target for non-hormonal contraceptives for both men and women.

A sperm ion channel required for sperm motility and male fertility

A characteristic of nerve cells is their ability to propagate an action potential and to communicate through specialized contact zones, called synapses. Synapses have received much attention from neurobiologists over the last 40 years, after their existence was ascertained by electron microscopy (De Robertis and Bennett 1954; Palade and Palay 1954). At the synapse, information is transferred from one cell to the contiguous one by neurotransmitters, viz. acetylcholine, biogenic amines and amino acids, or neuromodulators. These are mostly small peptides acting either alone or in combination (Furness et al. 1988; H6kfelt 1992). Thus, nerve cells communicate mostly by the intermediary of chemical signals. These important concepts have had a tremendous impact on the \"Zeitgeist\" of the neurosciences and have led many scientists to try to unravel the exact mechanisms of synaptic transmission. Furthermore, the discovery that the symptoms in Parkinson's disease are the consequence of a decrease in the concentration of the neurotransmitter dopamine in the basal ganglia, and that an improvement can be achieved by a dopamine precursor that passes through the blood-brain barrier (Hornykiewicz 1966), has helped to shape the opinion that many neurological and psychiatric diseases can be explained as defects in neurotransmitter systems. In the meantime, major efforts have been directed at understanding the way in which neurotransmitters

Calcium-binding proteins: selective markers of nerve cells.

Transient receptor potential (TRP) channels are a large family of ion channel proteins, surpassed in number in mammals only by voltage-gated potassium channels. TRP channels are activated and regulated through strikingly diverse mechanisms, making them suitable candidates for cellular sensors. They respond to environmental stimuli such as temperature, pH, osmolarity, pheromones, taste, and plant compounds, and intracellular stimuli such as Ca2+ and phosphatidylinositol signal transduction pathways. However, it is still largely unknown how TRP channels are activated in vivo. Despite the uncertainties, emerging evidence using TRP channel knockout mice indicates that these channels have broad function in physiology. Here we review the recent progress on the physiology, pharmacology and pathophysiological function of mammalian TRP channels.

https://pharmrev.aspetjournals.org/content/pharmrev/62/3/381.full.pdf

International Union of Basic and Clinical Pharmacology. LXXVI. Current Progress in the Mammalian TRP Ion Channel Family

A proper dialogue between spermatozoa and the egg is essential for conception of a new individual in sexually reproducing animals. Ca(2+) is crucial in orchestrating this unique event leading to a new life. No wonder that nature has devised different Ca(2+)-permeable channels and located them at distinct sites in spermatozoa so that they can help fertilize the egg. New tools to study sperm ionic currents, and image intracellular Ca(2+) with better spatial and temporal resolution even in swimming spermatozoa, are revealing how sperm ion channels participate in fertilization. This review critically examines the involvement of Ca(2+) channels in multiple signaling processes needed for spermatozoa to mature, travel towards the egg, and fertilize it. Remarkably, these tiny specialized cells can express exclusive channels like CatSper for Ca(2+) and SLO3 for K(+), which are attractive targets for contraception and for the discovery of novel signaling complexes. Learning more about fertilization is a matter of capital importance; societies face growing pressure to counteract rising male infertility rates, provide safe male gamete-based contraceptives, and preserve biodiversity through improved captive breeding and assisted conception initiatives.

https://www.physiology.org/doi/pdf/10.1152/physrev.00028.2010

Calcium Channels in the Development, Maturation, and Function of Spermatozoa

Ion channels are extraordinarily efficient machines that move ions in diversely controlled manners, allowing cells to rapidly exchange information with the outside world and with other cells. Communication is the currency of fertilization, as it is of most fundamental cell signaling events. Ion channels are deeply involved in the dialogue between sperm, its surroundings, and the egg. How sperm swim, find the egg and fertilize it depend on ion permeability changes modulated by environmental cues and components of the egg outer layer. Different ion channels distinctly localized in these tiny, amazing cells perform specific decoding functions that shape the sophisticated behavior of sperm. It is not surprising that certain sperm ion channels are turning out to be unique. New strategies to characterize sperm ion transport have opened exciting possibilities to dissect sperm-egg signaling and unveil novel contraception targets.

https://rep.bioscientifica.com/downloadpdf/journals/rep/131/6/1310977.pdf

Sperm channel diversity and functional multiplicity

Ion Transport in Sperm Signaling

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/S0014-5793%2801%2903134-9

Identification of mouse trp homologs and lipid rafts from spermatogenic cells and sperm

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2896%2900515-7

Claudia L. Treviño

Papers

Calcium Channels in the Development, Maturation, and Function of Spermatozoa

Sperm channel diversity and functional multiplicity

Ion Transport in Sperm Signaling

Identification of mouse trp homologs and lipid rafts from spermatogenic cells and sperm

T-type Ca2+ channels and α1E expression in spermatogenic cells, and their possible relevance to the sperm acrosome reaction