Fig 1.

Presenilin-mediated regulation of the intracellular Ca²⁺ homeostasis. A scheme illustrating the mechanisms underlying intracellular regulation of [Ca²⁺]_i. Ca²⁺ ions enter the cytosol through ligand-gated, voltage-gated or store-operated Ca²⁺ channels in the cell membrane. In addition, they are released from the intracellular Ca²⁺ stores of the ER via IP₃ receptor channels (IP₃R) or ryanodine receptor-channels (RyR). IP₃ is produced from phosphatidylinositol-4,5-bisphosphate (PIP₂) by PLC in response to the activation of metabotropic receptors (R). Intracellular Ca²⁺ levels (30–100 nM at rest, [130]) are controlled by plasma membrane Ca²⁺ pumps and by SERCAs. Presenilins are located both within the plasma membrane and the ER membrane and interact with many important elements of the Ca²⁺ signalling cascade (as indicated). Familiar AD mutations in presenilins (i) potentiate PLC activity, (ii) increase Ca²⁺ release through both IP₃ and ryanodine receptors and (iii) modulate activity of SERCA pumps. In addition, presenilins may function as Ca²⁺ leak channels of the ER (indicated). AD-related mutations in presenilins have been shown to render these leak channels non-functional, thereby causing an overload of the ER Ca²⁺ stores.