Potassium calcium-activated channel subfamily U member 1 (Slo3) (Slo3)

Potassium calcium-activated channel subfamily U member 1 (Slo3) is a sperm-specific potassium channel that is essential for male fertility (UniProt A8MYU2). It is primarily regulated by intracellular pH and membrane voltage, and in humans, it also exhibits sensitivity to intracellular calcium levels (PubMed 24670955). Slo3 mediates the membrane hyperpolarization that occurs during sperm capacitation, a critical process that enables the sperm to undergo the acrosome reaction and achieve hyperactivated motility required to fertilize an oocyte (PubMed 23129643). Genetic mutations in the KCNU1 gene, which encodes Slo3, have been linked to cases of idiopathic male infertility and asthenoteratozoospermia (PubMed 34980136). Due to its highly restricted expression in the testes and sperm, Slo3 is considered a primary target for the development of non-hormonal male contraceptives (PNAS 2023, 120(4): e2212338120). Selective small-molecule inhibitors, such as VU0546110, have demonstrated the ability to block human sperm hyperpolarization and prevent fertilization in vitro, suggesting a high potential for therapeutic development with minimal off-target effects (PubMed 36649429).

Other names

KCNU1KCa5.1KCNMC1KCNMA3Slowpoke homolog 3KSper

Inhibition of potassium efflux through Slo3 prevents sperm membrane hyperpolarization, thereby blocking the capacitation and acrosome reaction required for fertilization.