Novel signalling mechanism and clinical applications of sperm-specific PLCζ

Egg activation is the first step of embryonic development and in mammals is triggered by a series of cytoplasmic calcium (Ca2+) oscillations. Sperm-egg fusion initiates these Ca2+ oscillations by introducing a sperm-specific protein factor into the egg cytoplasm. Substantial evidence indicates that this protein is a sperm-specific phospholipase C (PLC), termed PLC-zeta (PLC zeta). PLC zeta stimulates cytoplasmic Ca2+ oscillations matching those at fertilization triggering early embryonic development in several mammalian species. Structurally, PLC zeta is comprised of four EF-hands, a C2 domain, and X and Y catalytic domains. PLC zeta is an unusual PLC since it lacks a pleckstrin homology (PH) domain. It is also distinctive in that its X-Y linker is not involved in auto-inhibition of catalytic activity, but instead binds to phosphatidylinositol 4,5-bisphosphate (PIP2). Moreover, relative to other PLC isoforms, PLC zeta possesses unique potency in stimulating Ca2+ oscillations in eggs, although it does not appear to bind to plasma membrane PIP2. In contrast, PLC zeta appears to interact with intracellular vesicles in eggs that contain PIP2. I discuss the recent advances in our knowledge of the intriguing biochemical and physiological properties of sperm PLC zeta and postulate potential roles for PLC zeta in terms of clinical diagnosis and therapy for certain forms of male infertility.