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 (PLCζ). PLCζ stimulates cytoplasmic Ca²⁺ oscillations matching those at fertilization triggering early embryonic development in several mammalian species. Structurally, PLCζ is comprised of four EF-hands, a C2 domain, and X and Y catalytic domains. PLCζ 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, PLCζ possesses unique potency in stimulating Ca²⁺ oscillations in eggs, although it does not appear to bind to plasma membrane PIP₂. In contrast, PLCζ 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 PLCζ and postulate potential roles for PLCζ in terms of clinical diagnosis and therapy for certain forms of male infertility.