AKAP3 mediated type I PKA Signaling is required for mouse sperm Hyperactivation and fertility

Biol Reprod. 2023 Dec 25:ioad180. doi: 10.1093/biolre/ioad180. Online ahead of print.ABSTRACTProtein kinase A (PKA) signaling pathway which mediated protein phosphorylation is important for sperm motility and male fertility. This process relies on A-kinase anchoring proteins (AKAPs) that organize PKA and its signalosomes within specific subcellular compartments. Previously, it was found that the absence of AKAP3 leads to multiple morphological abnormalities in mouse sperm. But how AKAP3 regulates sperm motility is yet to be elucidated. AKAP3 has two amphipathic domains, Dual and RI in its N-terminus. These domains are responsible for binding RIα and RIIα regulatory subunits of PKA and for RIα only, respectively. Here, we generated mutant mice lacking the Dual and RI domains of AKAP3. It was found that the deletion of these domains caused male mouse infertile, accompanied by mild defects in the fibrous sheath (FS) of sperm tails. Additionally, the levels of serine/threonine phosphorylation of PKA substrates and tyrosine phosphorylation decreased in the mutant sperm, which exhibited a defect in hyperactivation under capacitation conditions. Notably, the protein levels of PKA subunits remained unchanged. But, interestingly, the regulatory subunit RIα was mis-localized from principal piece to midpiece of sperm tail, whereas this was not observed for RIIα. Further protein-protein interaction assays revealed a preference for AKAP3 to bind RIα over RIIα. Collectively, our fin...
Source: Biology of Reproduction - Category: Reproduction Medicine Authors: Source Type: research