Purinergic signaling in testes revealed

The Rockefeller University Press $30.00 J. Gen. Physiol. 2016 Vol. 148 No. 3 207–211 www.jgp.org/cgi/doi/10.1085/jgp.201611676 207 Key physiological functions of organisms, such as sensory transduction, regulation of heart rate, smooth muscle contraction, bile secretion, endocrine regulation, immune responses, and various pathophysiological conditions, including neuropathic pain, diabetes, kidney failure, and cancer, are regulated by purinergic signaling (Burnstock, 2013). The pathway begins with extracellular purine nucleotides, such as ATP and UTP, or nucleosides, such as adenosine, binding to their cognate purinergic receptors in the plasma membrane (Burnstock, 1972). Purinergic receptors are divided into two types: ligand-gated ion channels (P2X) and G protein–coupled receptors (P2Y and P1). Whereas P1 is activated specifically by adenosine, P2Y receptors are activated by a wide range of nucleotides, including ATP, ADP, and UTP, among others. P2X receptors are specifically activated by ATP and are further divided into seven different subtypes: P2X1 to P2X7. P2X receptors form homomeric or heteromeric trimers (Jiang et al., 2003; Kawate et al., 2009), thus resulting in nonselective ATPgated ion channels that are permeable to Ca, Na, and K (Fig. 1). An important role for P2X receptors in male fertility has been proposed after the detection of several members of the P2X family in mammalian spermatozoa (Banks et al., 2010). In the well-executed study reported in this issue, Fleck et al. perform electrophysiological profiling of murine spermatogonia and describe functional expression of two types of purinergic receptors, P2X4 and P2X7, as well as large-conductance Ca-activated K (BK, or “Big Potassium”) channels, in immature male germ cells. ATP is known to mediate an increase in intracellular calcium concentration in sperm and also to stimulate the acrosome reaction, in which enzymes stored in the anterior cap-like structure of the sperm head are released, allowing sperm to penetrate the egg (Luria et al., 2002). The P2X2 receptor was recently characterized in mouse sperm (Navarro et al., 2011). P2rx2-deficient mice are fertile and have normal sperm morphology; however, their fertility declines over days with frequent mating, suggesting that the P2X2 receptor can provide a selection advantage under certain conditions. P2X receptors are also involved in sperm transport through vas deferens: double deletion of P2X1 and α1A-adrenergic G protein–coupled receptors in male mice led to a complete infertility caused by inhibition of sperm transport (White et al., 2013). P2X receptors have also been reported to be expressed in mammalian testes (Glass et al., 2001); however, their physiological importance for spermatogenesis and sperm maturation attracted attention only recently. In this issue, Fleck et al. (2016) perform a comprehensive evaluation of the physiological function of P2X4 and P2X7 receptors, as well as BK channels, in mammalian spermatogonial cells, the undifferentiated germ cells that produce spermatozoa. This work reveals new insights into autocrine/paracrine regulation of mammalian spermatogenesis. The authors suggest that spermatogonial purinergic signaling might be required for synchronized sperm development and release into the epididymis (Fleck et al., 2016). The important determinant of male fertility is sperm count; therefore, testes are required to produce a steady number of spermatozoa to provide continuous sperm transport through the male reproductive tract. The testis is an immune-privileged organ in which Sertoli cells prevent spermatogonia and developing sperm cells from direct contact with the blood. Thus, spermatogonia lack the ability to coordinate their division through direct communication via the blood stream. Paracrine signaling, using ATP, could therefore be a useful alternative mechanism to solve this communication problem and ensure coordinated and synchronized sperm development and release. ATP could be released by either spermatogonia or adjacent Sertoli cells, resulting in effective intercellular communication. The current work by Fleck et al. (2016) raises an interesting question about whether synchronized sperm maturation is under the control of purinergic paracrine/autocrine signaling in adult testes.