. Author manuscript; available in PMC: 2016 Sep 1.

Published in final edited form as: Cell Metab. 2015 Jul 16;22(3):381–397. doi: 10.1016/j.cmet.2015.06.010

Table 1.

Proteins regulating Ca²⁺ homeostasis in the ER and mitochondria

Name	Isoforms	Tissue Expression	Function	Location	Main Regulators	Knockout Phenotype	References
SERCA	SERCA 1a	Skeletal Muscle/brown adipose tissue	Ca²⁺ uptake from cytosol to ER lumen	ER membrane	Endogenous: Sarcolipin (skeletal muscle and heart) (reversible inhibitor) Phospholambam (skeletal muscle and heart) (reversible inhibitor) Pharmacological: Thapsigargin (inhibitor) Cyclopiazonic acid (reversible inhibitor) BHQ (inhibitor)	Gasping respiration, cyanotic phenotype, and postnatal lethality	(de Meis and Vianna, 1979; Prasad et al., 2004; Toyoshima and Inesi, 2004; Wu et al., 1995)
	SERCA 1b	Skeletal muscle
	SERCA 2a	Skeletal muscle/heart				Embryonic lethality
	SERCA 2b	Ubiquitous including liver and adipose tissue				Embryonic lethality
	SERCA 3	Non-muscle tissues including blood cells, epithelial cells and respiratory tract, pancreatic β cells				No gross phenotype	(Vandecaetsbeek et al., 2011)
IP3R	IP3R1	Ubiquitous, predominantly in brain	Ca²⁺ release from ER to cytosol	ER membrane	Endogenous: IP3 Low Ca²⁺ levels (activator) High Ca²⁺ levels (inhibitor) ATP Regulatory kinases: PKA,PKC,AKT,PKG,CaMkinase Protein interaction: Numerous proteins Pharmacological: Xestopongin C (inhibitor)	Neurological defects and early lethality	(Choe and Ehrlich, 2006; Foskett et al., 2007)
	IP3R2	Ubiquitous. Represents the predominant isoform in liver and adipose tissue				IP3R2^−/− exhibits some cardiac dysfunction. IP3R2/IP3R3 double deficiency leads to defective saliva and gastric juice secretion
	IP3R3	Various tissues and culture cell
RyaR	RyR1	Muscle (predominantly skeletal)/brain	Ca²⁺ release from ER to cytosol	ER membrane	Endogenous: Low Ca²⁺ levels (activator) High Ca²⁺ levels (inhibitor) Kinase proteins: PKA, PKG and CaMKinase High Mg⁺ (inhibitor) Pharmacological: Low Ryanodine levels (activator) High Ryanodine levels (inhibitor) Caffeine (activator) Rutheniun Red (inhibitor)	Perinatal lethality with gross abnormalities of skeletal muscle	(Fill and Copello, 2002; Meissner, 1994; Van Petegem, 2012)
	RyR2	Muscle (predominantly heart)/brain				Embryonic lethality (~e10) with morphologic abnormalities in the heart tube
	RyR3	Predominantly brain				Fertile and displays no gross abnormalities. Increased locomotor activity
STIM	STIM1	Ubiquitous, predominant isoform in most tissues	Ca²⁺ entry from extracellular space to cytosol	ER membrane	Endogenous:Ca²⁺ (depletion activates) ROS (activates) Temperature (high temperature activates) Hypoxia (activates) Regulatory Kinases: SGK1, AMPK Pharmacological: Low 2APB levels (activate) High 2APB levels (inhibit)	Embryonic or perinatal lethality with respiratory failure	(Carrasco and Meyer, 2011; Soboloff et al., 2012)
STIM	STIM2	Ubiquitous, prevailing isoform in brain and dendritic cells	Ca²⁺ entry from extracellular space to cytosol	ER membrane		Lethality at 4–5 weeks of age	(Carrasco and Meyer, 2011; Soboloff et al., 2012)
Orai	Orai1	Ubiquitous, predominant skin and lymphocytes	Ca²⁺ entry from extracellular milieu to cytosol, coupled with STIM	Plasma membrane	Pharmacological: lanthanides Gd³⁺ and La³⁺ (inhibitors)	Smaller size, eyelid irritation, and sporadic hair loss; immune system, lymphocyte development is normal but T- and B-cell function is impaired.	(Cao et al., 2015; Gwack et al., 2008; Hogan et al., 2010)
	Orai2	Ubiquitous				-----
	Orai3	Ubiquitous				-----
Calreticulin		Ubiquitous	Ca²⁺-binding Chaperone	ER lumen		Embryonic lethality due to impaired cardiac development. Fibroblast cells derived from calreticulin-deficient embryos show significantly reduced ER Ca²⁺ capacity.	(Michalak et al., 2009; Prins and Michalak, 2011)
Calnexin		Ubiquitous	Ca²⁺-binding Chaperone	ER lumen		50% lethality within the first 48h after birth, and the cause of the death remains to be determined. The survivors exhibit motor abnormalities.	(Caramelo and Parodi, 2008; Prins and Michalak, 2011)
VDAC	VDAC1	Ubiquitous and the most abundant isoform	Forms a channel through the mitochondrial outer membrane and allows diffusion of small hydrophilic molecules such as Ca²⁺	OMM	Endogenous: Interacting proteins: HK, Bcl2 ROS Phosphorylation: PKA PKCe Pharmacological: Ruthenium red (inhibitor) Pharmacological: Ru360 (inhibitor)	Defects in skeletal muscle. Modifications of kinetic parameters of some mitochondrial enzymes and mitochondrial ultrastructure abnormalities. No major functional deficits	(Colombini, 2012; Messina et al., 2012; Shoshan-Barmatz and Ben-Hail, 2012)
	VDAC2	Ubiquitous				------
	VDAC3	Ubiquitous				Male infertility and altered mitochondrial ultrastructure.
MCU		Ubiquitous	Ca²⁺uptake into the mitochondria	IMM	Endogenous: Interacting proteins: MICU1/MICU2/MICUR1/EMRE Pharmacological: Ru360 (inhibitor)	Dependent on the genetic background. MCU knockout mice on a mixed background are viable , mitochondria Ca²⁺ uptake by isolated mitochondria and cells of this animals are blunted but their respiratory capacity and morphology are normal. Also the animals don’t show any gross phenotype except impaired skeletal muscle performance under situations requiring high-energy expenditure.	(Chaudhuri et al., 2013; De Stefani et al., 2011; De Stefani and Rizzuto, 2014; Foskett and Philipson, 2015)
Na⁺/Ca²⁺ channel, NCLX	NCLX	Ubiquitous	Ca²⁺ efflux from the mitochondria to the cytosol	Mitochondrial inner membrane	Endogenous: K⁺ (activator) Ni²⁺, Mg²⁺, Ba²⁺ and La³⁺ (inhibitor) Kinase proteins: PKC, PINK1		(Palty et al., 2012)