Calreticulin, Ca2+, and calcineurin - signaling from the endoplasmic reticulum.
Calcium (Ca2+) is a universal signalling molecule involved in many aspects of cellular function. The majority of intracellular Ca2+ is stored in the endoplasmic reticulum and once Ca2+ is released from the endoplasmic reticulum, specific plasma membrane Ca2+ channels are activated, resulting in increased intracellular Ca2+. In the lumen of the endoplasmic reticulum, Ca2+ is buffered by Ca2+ binding chaperones such as calreticulin. Calreticulin-deficiency is lethal in utero due to impaired cardiac development and in the absence of calreticulin, Ca2+ storage capacity within the endoplasmic reticulum and inositol 1,4,5-trisphosphate (InsP3) receptor mediated Ca2+ release from the endoplasmic reticulum are compromised. Over-expression of constitutively active calcineurin in the heart rescues calreticulin-deficient mice from embryonic lethality. This observation indicates that calreticulin is a key upstream regulator of calcineurin in Ca2+-signalling pathways and highlights the importance of the endoplasmic reticulum and endoplasmic reticulum-dependent Ca2+ homeostasis for cellular commitment and tissue development during organogenesis. Furthermore, Ca2+ handling by the endoplasmic reticulum has profound effects on cell sensitivity to apoptosis. Signalling between calreticulin in the lumen of the endoplasmic reticulum and calcineurin in the cytoplasm may play a role in the modulation of cell sensitivity to apoptosis and the regulation of Ca2+-dependent apoptotic pathways.
Groenendyk
Jody
J
Canadian Institutes of Health Research Membrane Protein Research Group and the Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
Lynch
Jeffrey
J
Michalak
Marek
M
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D037282:Calreticulin / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D051379:Mice; D009206:Myocardium / Q000378:metabolism
D015220:Calcium Channels; D037282:Calreticulin; D015544:Inositol 1,4,5-Trisphosphate; D019703:Calcineurin; D002118:Calcium