The role of CALHM1 in calcium signaling: Relevance for APP metabolism and AD pathogenesis. CALHM1 is a cell surface protein of neuronal origin that shares sequence similarities with NMDAR. CALHM1 expression generates a calcium-selective cation current at the plasma membrane and controls cytosolic calcium concentrations, a mechanism that may lead to ERK1/2 activation (left panel). Importantly, the P86L mutation in CALHM1, which we found associated with an increased risk for AD in European populations, leads to an inhibition of the control of APP processing by CALHM1 (right panel). Consequently, the P86L mutation leads to a derepression of the effect of CALHM1 on Aβ accumulation and thus to an increase of Aβ levels. P86L-CALHM1 promotes Aβ accumulation via a loss of CALHM1 control on calcium permeability and cytosolic calcium levels . Therefore, CALHM1 is a component of a novel cerebral calcium channel family involved in calcium signaling and Aβ metabolism, and thus may represent an important player in the calcium homeostasis deregulations observed in AD pathogenesis.