Molecular Identity of Human Sperm Potassium Channel and Its Role in Male Fertility

Potassium channels are indispensable for normal cell physiology because they regulate cell membrane potential. Murine spermatozoa possess a pH-sensitive sperm K+ channel, Slo3, which is essential for male fertility in mice. It has been assumed, but never been proven, that the K+ channel of human sperm has a similar molecular identity. However, according to our data this is not the case.  We have found that the physiological properties of the human sperm K+ channel differ dramatically from that of mouse. This project seeks to reveal the molecular identity of human sperm Kchannel, study its regulation, and explain the role of sperm K+ channels in human physiology. 

Our preliminary data strongly indicate involvement of the big conductance (BK) potassium channel Slo1 in human sperm physiology—an unconventional role for this type of channel. The Slo1 ion channel is ubiquitously expressed in many human tissues and mutations in this channel are associated with various syndromes and diseases including: paroxysmal dyskinesias, erectile dysfunction, type 2 diabetes, incontinence, asthma, epilepsy, cardiovascular diseases, and diastolic hypertension. Therefore, illuminating the role of the Slo1 channel in male fertility and linking the malfunction of this channel to reduced male fertility associated and several of the above mentioned diseases, will provide a better picture of the role of this channel in the human body.

The results obtained from this project will help to identify the molecules essential for potassium homeostasis in sperm cells, may lead to improved diagnostics and treatment of male infertility, and provide new targets for male contraception.



Role of human KSper (Slo1) in sperm physiology.

In the uterus and fallopian tube, CatSper is partially activated due to the intracellular alkalinization evoked by proton extrusion through Hv1 and picomolar- to nanomolar progesterone (P) concentrations. However, to achieve full activation of CatSper, flagellar plasma membrane must be depolarized. This is achieved by the inhibition of sperm KSper, the channel responsible for membrane hyperpolarization. In close proximity to the oocyte, spermatozoa encounter micromolar concentrations of P, which inhibit hKSper, resulting in membrane depolarization. These events allow full activation of CatSper, trigger sperm hyperactivation, allow spermatozoa to penetrate through the egg protective vestment, and make fertilization possible.



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