Minerals:Calcium: Ca2+

Minerals

Calcium: Ca²⁺

Calcium ion (Ca²⁺) is an extremely critical mineral required for a vast array of biochemical processes. Some of the most wide-spread functions for this ion are its requirements for neural signaling, cell proliferation, bone mineralization, cardiac function, muscle contraction, digestive system function, and secretory processes. In the context of Ca²⁺ in secretion, the ion is required for neurotransmitter release and hormone release from a number of different tissues. In addition, calcium is necessary for proper activity of a number of proteins involved in blood coagulation. Calcium concentrations in the blood are very tightly regulated within a narrow range. Within the blood over half of the Ca²⁺ is free while the rest is bound to albumin or complexed with other ions such as bicarbonate and phosphate.
Calcium functions both intracellularly and extracellularly. As an intracellular ion, Ca²⁺ serves the role of a second messenger. The difference between the Ca²⁺ concentration outside the cell, within the interstitial fluids, is on the order of 12,000 times that of the free intracellular concentration. This difference creates an inwardly directed electrical gradient as well as allowing for dramatic influxes of the ion in response to a variety of cellular stimuli. Within the cell, most calcium is not free in the cytosol but is stored within the endoplasmic reticulum (ER) and other microsomal (membrane) compartments. This calcium is able to be rapidly mobilized to the cytosol via the activation of ligand-gated ion channels. One of the most significant events resulting in intracellular calcium release is the plasma membrane receptor-mediated activation of phospholipase Cβ (PLCβ) in response to ligand (e.g. hormone) binding. Active PLCβ, in turn, hydrolyzes membrane phosphatidylinositol-4,5-bisphosphate (PIP₂) into diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP₃). IP₃ binds to receptors in the ER, activating the inherent calcium channel of the receptor leading to the flooding of the cytosol with free calcium.
Humans express three distinct IP₃ receptors encoded by the ITPR1, ITPR2, and ITPR3 genes. The ITPR1 gene is located on chromosome 3p26.1 and is composed of 63 exons that generate three alternatively spliced mRNAs encoding three distinct isoforms of the receptor. ITPR1 isoform 1 is a 2710 amino acid protein, isoform 2 is a 2695 amino acid protein, and isoform 3 is a 2743 amino acid protein. The ITPR2 gene is located on chromosome 12p11.23 and is composed of 62 exons that encode a 2701 amino acid protein. The ITPR3 gene is located on chromosome 6p21.31 and is composed of 60 exons that encode a 2671 amino acid protein. Each of the IP₃ receptors possess a cytoplasmic N-terminal ligand-binding domain and is comprised of six membrane-spanning helices that forms the core of the ion pore. Once released, the free calcium interacts with a variety of proteins activating a series of biochemical reactions specific to the particular cell type and the signal initiating the calcium release.
Calcium exerts many of its biochemical effects by binding to Ca²⁺-binding proteins, several of the most significant are outlined in the following Table. The vast majority of proteins, whose activities are controlled by Ca²⁺ binding, contain a structural motif referred to as the EF-hand. The EF-hand domain consists of two regions of α-helix linked by a short (usually 12 amino acids) loop region. These EF-hand proteins are found both intracellularly and extracellularly. The superfamily of human EF-hand domain containing proteins consists of 222 proteins with an additional subset of four actinin proteins included in the superfamily. The total number of proteins that bind calcium is beyond the scope of this discussion but several important examples of intracellular Ca²⁺-binding proteins include the calmodulins, calcineurins, calbindins, and troponins, whereas important extracellular Ca²⁺-binding proteins include the coagulation factors [II (prothrombin), VII, IX, X, protein C, protein S] and the cell-cell communication/adhesion proteins of the cadherin family.

Examples of Important Calcium-Binding and Regulated Proteins

Protein Name	Functions / Comments
Calbindins	refers to a family of Ca2+-binding proteins; original member identified in chickens as vitamin D-dependent calcium-binding protein and then called calbindin-D28K (encoded by the CALB1 gene); other members include calretinin (29kDa protein encoded by CALB2 gene) and calbindin-D9K (encoded by the S100G gene which is also referred to as CALB3); all members mediate Ca2+ transport across membranes; in humans the CALB1 encoded protein is involved in renal Ca2+ reabsorption; in humans the S100G (CALB3) encoded protein is required for mediating intestinal calcium absorption in response to hormonal action of calcitriol; CALB2 encodes a neural-specific Ca2+-binding protein; S100G (CALB3) is a member of the S100 family of proteins of which there are 24 members each of which function in some capacity related to the regulation of proliferation, differentiation, apoptosis, Ca2+ homeostasis, energy metabolism, inflammation and migration/invasion
Calcineurins	these proteins are components of a Ca2+-dependent serine/threonine phosphatase identified as protein phosphatase 3, PP3 (formerly PP2B); calcineurins consists of a catalytic subunit and a regulatory subunit, and a subunit of calmodulin; the catalytic subunit is encoded by one of three genes: PPP3CA (commonly called calcinuerin A, CALNA), PPP3BB (commonly called calcineurin B, CALNB), and PPP3CC (commonly called calcineurin); the regulatory subunit is encoded by one of two genes: PPP3R1 and PPP3R2; activity of the calcineurins also requires Zn2+ and Fe3+ binding to domains in the catalytic subunits; major cell types regulated by calcineurin activity are T cells, neural cells, and cardiac cells; within the brain the primary substrates for calcineurin activity are Ca2+ channels, the dephosphorylation of which leads to their inactivation, thereby modulating the release of various neurotransmitters; calcineurin is potently inhibited by the immunosuppressant drugs, cyclosporin A and FK506 (fujimycin)
Calmodulins	these proteins are regulatory subunits of numerous enzymes, particularly kinases; humans express three distinct calmodulin genes identified as CALM1, CALM2, and CALM3; the proteins possess four Ca2+-binding sites; several kinase families are known to possess calmodulin subunits: glycogen synthase-glycogen phosphorylase kinase (PHK, composed of six subunits, the δ-subunit is calmodulin), myosin light-chain kinases (four isoforms: MYLK or MLCK in smooth muscle, MYLK2 in skeletal muscle, MYLK3 in cardiac muscle, and MYLK4), and the kinases termed Ca2+/calmodulin (CaM)-dependent protein kinases (CaMK) which includes CaMKI, CaMKII, CaMKIII, and CaMKIV; CaMKIII is more commonly referred to as eEF-2 kinase (eEF-2K) involved in the regulation of protein synthesis; in addition to serving as calcium-sensing regulatory subunits of numerous kinases, calmodulins also regulate the activity of protein phosphatases (particularly PP3 as indicated above) and the nitric oxide synthases, NOS
Troponins	the troponins are actually heterotrimeric complexes of three distinct subunits: troponin C (TnC), troponin I (TnI), and troponin T (TnT); TnT and TnI exist in tissue specific isoforms with the cardiac muscle forms identified as cTnI and cTnT, whereas the skeletal muscle forms are skTnI and skTnT; TnC is the Ca2+-binding subunit whose role is to effect the Ca2+-dependent regulation of muscle contraction; TnI inhibits the ATPase activity of the actin-myosin complex of the thin filaments that control muscle fiber contraction; TnT binds tropomyosin, thereby regulating troponin complex interaction with thin filaments; measurement of plasma levels of cTnI is now considered the standard for determination of diseases/disorders related to cardiac function such as acute myocardial infarction (AMI)
PKC family	the protein kinase C (PKC) family of serine/threonine kinases is composed of several related enzymes (for a more detailed discussion go to the Signal Transduction page); PKC enzymes are divided into three subfamilies termed conventional (cPKC), novel (nPKC), and atypical (aPKC); it is only the conventional PKC subfamily of enzymes that is regulated by calcium ions