Male infertility constitutes a serious problem contributing to half of all infertility cases worldwide. At least 50% of male infertility cases are considered idiopathic. This huge gap in our understanding of male infertility is partially attributd to our insufficient knowledge of human sperm cell physiology and to the unknown identity of human sperm ion channels. Ion channels are indispensable for sperm physiology: they regulate sperm motility, chemotaxis toward the egg and the acrosome reaction. Mammalian spermatozoa gain competence to fertilize an oocyte as they travel through the female genital tract. This progression is termed capacitation and is accompanied by: 1) sperm intracellular alkalinization, evoked by proton extrusion through proton channels; 2) elevation of the intracellular [Ca2+], evoked by calcium influx through calcium ion channels, and 3) membrane hyperpolarization that is evoked by K+ efflux. Whereas the proton and calcium channels of human sperm are identified as Hv1 and CatSper, the principal potassium channel of human sperm (hKSper) is unknown. Potassium channels are indispensable for normal sperm physiology since they regulate cell membrane potential and cell motility. In mice, pH-sensitive sperm K+ channel, coded by the KCNU1 gene is regulated by intracellular alkalinization and is essential for male fertility. It has been assumed, but never been proven that the K+ channel of human sperm has similar molecular identity. According to our preliminary data it is not the case, and hKSper likely has different molecular identity. This project will reveal the precise molecular identity of human sperm potassium channel, will study the regulation of this channel, and explain the role of potassium channels during human sperm development, maturation and fertilization. The knowledge gained from the proposed research will fill in gaps in our understanding of the basic mechanisms underlying the development of human sperm, will help to identify the molecules essential for potassium homeostasis in sperm cells, will lead to the creation of novel diagnostic tests for male fertility, and reveal new targets for contraception.

Public Health Relevance

Potassium channels are indispensable for normal cellular physiology, and while identity of the K+ channel of mouse sperm is well known, the molecular composition and regulation of the principal potassium channel of human sperm is not well understood, and moreover, differs dramatically from that of mouse. This project will reveal the molecular identity of human sperm potassium channel, and shed the light on its regulation. The results obtained from the proposed research will help to identify the molecules essential for potassium homeostasis in human sperm cells, may lead to improved diagnostics and infertility treatment, and provide new targets for male contraception.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Biophysics of Neural Systems Study Section (BPNS)
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Nie, Zhongzhen
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University of California Berkeley
Schools of Arts and Sciences
United States
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Mannowetz, Nadja; Mundt, Nadine; Lishko, Polina V (2018) Reply to Brenker et al.: The plant triterpenoid pristimerin inhibits calcium influx into human spermatozoa via CatSper. Proc Natl Acad Sci U S A 115:E347-E348
Lishko, Polina V; Mannowetz, Nadja (2018) CatSper: A Unique Calcium Channel of the Sperm Flagellum. Curr Opin Physiol 2:109-113
Mundt, Nadine; Spehr, Marc; Lishko, Polina V (2018) TRPV4 is the temperature-sensitive ion channel of human sperm. Elife 7:
Miller, Melissa R; Kenny, Samuel J; Mannowetz, Nadja et al. (2018) Asymmetrically Positioned Flagellar Control Units Regulate Human Sperm Rotation. Cell Rep 24:2606-2613
Mannowetz, Nadja; Miller, Melissa R; Lishko, Polina V (2017) Regulation of the sperm calcium channel CatSper by endogenous steroids and plant triterpenoids. Proc Natl Acad Sci U S A 114:5743-5748
Brown, Sean G; Publicover, Stephen J; Mansell, Steven A et al. (2016) Depolarization of sperm membrane potential is a common feature of men with subfertility and is associated with low fertilization rate at IVF. Hum Reprod 31:1147-57
Björkgren, Ida; Lishko, Polina V (2016) Purinergic signaling in testes revealed. J Gen Physiol 148:207-11
Miller, Melissa R; Mannowetz, Nadja; Iavarone, Anthony T et al. (2016) Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone. Science 352:555-9
Syeda, Shameem Sultana; Carlson, Erick J; Miller, Melissa R et al. (2016) The Fungal Sexual Pheromone Sirenin Activates the Human CatSper Channel Complex. ACS Chem Biol 11:452-9
Lishko, Polina V (2016) Contraception: Search for an Ideal Unisex Mechanism by Targeting Ion Channels. Trends Biochem Sci 41:816-818

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