Adapted from the original article in Pharmacological Reviews

Introduction

CatSper channels (CatSper1-4) are named after the first putative cation channel of sperm [7,9]. CatSpers are putative six-transmembrane (6TM) voltage-gated Ca²⁺-permeant channels and seem to be specific to sperm cells. CatSper1 and 2 are each essential for the hyperactivation of sperm cell motility, which is required for fertility. Sequence identities among these CatSper family members range between 22 and 27% across the ion transport domain [5].

Structural Features

All CatSpers are most closely related to the 6TM voltage-gated sodium channel (Na_VBP) in bacteria, with the next closest relatives being the large mammalian Ca_V and Na_V channel classes (Fig. 1). CatSpers have an S4 transmembrane segment with positively charged amino acids interspersed between every three amino acids. CatSper1 also contains a remarkable abundance of histidine residues in its amino terminus.

FIG. 1. CatSper and TPC family tree. See introduction to TRP channels for more information.

Functional Features

CatSper1 is localized to the plasma membrane of the sperm tail [9]. Targeted disruption of the CatSper1 gene led to a male sterile phenotype in an otherwise normal mouse. Whereas the mating behavior, sperm count, and sperm cell morphology of the mutant mice were indistinguishable from those of the wild type, mutant sperm cells were sluggish, displayed reduced basal velocity, and lacked vigorous beating and bending in the tail region. Mutant sperm cells could not fertilize eggs with an intact zona pellucida but could fertilize eggs whose outer layers had been enzymatically removed [9]. Further studies showed that CatSper1-null sperm cells could not be hyperactivated [2]. Interestingly, depolarization evoked an increase in intracellular Ca²⁺ in wild-type sperm cells but not in CatSper1-null sperm cells [2]. CatSper2-null mice and sperm cells have an indistinguishable phenotype from CatSper1-null mice. Male mice lacking CatSper2 were also sterile due to the absence of the hyperactivated motility needed for penetration of the extracellular matrix of the egg [8]. In one study in humans, subfertile men with deficient sperm cell motility had significantly reduced expression of CatSper1 [6]. CatSper2 has been implicated by linkage analysis in human asthenoteratozoospermia [1].

Recently, spermatazoa were patch-clamped, and the CatSper1-dependent current was shown to be an alkaline-potentiated, voltage-activated, calcium-selective channel [4]. CatSpers have not yet been functional in numerous heterologous expression systems or spermatocytes, apparently because they are not targeted to the plasma membrane of nonsperm cells [9]. Little is known about CatSpers3 and 4.

Two-Pore Channels

The two-pore channels TPC1 and TPC2 are putative cation-selective ion channels related to CatSper and transient receptor potential channels and, more distantly, to Na_v and Ca_v channels. The TPCN1 (Hs.524763; Mm.114054) and N2 (Hs.503051; Mm.102235) genes encode proteins with two repeats of a 6TM domain. Each domain has a positively charged voltage sensor segment. TPC1 mRNA is detected at relatively high levels in kidney, liver, and lung, and immunohistochemistry of kidney shows that TPC1 was expressed in the inner medullary collecting ducts [3]. Neither TPC has been functionally expressed in heterologous cells to date, and no genetic data are available.

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