Membrane-mediated actions of 1,25-dihydroxy vitamin D3: A review of the roles of phospholipase A₂ activating protein and Ca²⁺/calmodulin-dependent protein kinase II

The secosteroid 1α,25-dihydroxy vitamin D3 [1α,25(OH)₂D₃] acts on cells via classical steroid hormone receptor-mediated gene transcription and by initiating rapid membrane-mediated signaling pathways. In its membrane-initiated pathway, after 1α,25(OH)₂D₃ interacts with protein disulfide isomerase, family A, member 3 (Pdia3) in caveolae, phospholipase A₂ (PLA₂) and protein kinase C (PKC) are activated. Recent efforts to determine the signaling proteins involved in the 1α,25(OH)₂D₃ signal from Pdia3 to PLA₂ have indicated that phospholipase A₂ activating protein (PLAA) and Ca²⁺/calmodulin-dependent kinase II (CaMKII) are required. PLAA is located in caveolae, where it interacts with Pdia3 and caveolin-1 (Cav-1) to initiate rapid signaling via CaMKII, activating PLA₂, leading to activation of protein kinase C (PKC) and PKC-dependent responses.