Proteins, regulated by binding of inorganic ions, are very important for different aspects of cell functioning.

There is a wide variety of Calcium, Manganese and Iron-regulated proteins inside and out of the cells.

Binding of Ca('2+) extracellular region to receptors of L-Glutamic acid: Glutamate receptor, metabotropic 1 (mGluR1) and Glutamate receptor, metabotropic 5 (mGluR5) is essential for receptor activation [1], [2]. In turn, mGluR1 and mGluR5 through G-protein alpha-q/ PLC-beta/ IP3 intracellular/ IP3 receptor promote release of Ca('2+) from internal endoplasmic reticulum Ca('2+) stores [3].

Binding of Ca('2+) cytosol is essential for activation of inflammatory proteins S100 calcium binding proteins A8 and A9 (Calgranulin A and Calgranulin B) [4], [5]. In turn, Ca('2+) cytosol activates S100 calcium binding proteins B and A4 (S100B and MTS1 (S100A4)), which regulate cell differentiation [6], [7].

Also, Ca('2+) cytosol is required for activation of Solute carrier family 8 (sodium/calcium exchanger), member 1 (NCX1), which transports Ca('2+) cytosol out of the cell, and imports Na('+) extracellular region inside the cell [8], [9]. Mn('2+) extracellular region inhibits NCX1 transporter activity [10], [11].

Ion transporter Apotransferrin, which is member of Transferrin group, and anti-apoptotic protein Prion protein (PRNP) are Mn('3+) extracellular region-binding proteins [12], [13]. Intracellular Mn('2+) Golgi lumen binds to Beta-1,3-glucuronyltransferase 1 (B3GA1), which is a regulator of carbohydrate metabolism [14].

Fe('3+) is transported in living organisms by ion transporters: Apotransferrin, Lactoferrin and Lipocalin 2 (NGAL) [15], [16], [17].

Fe('2+) cytosol is a regulator of several metabolic processes. Fe('2+) cytosol binds to Tyrosine hydroxylase (TY3H), important for tyrosine metabolism [18], [19]. Also, Fe('2+) cytosol activates Tryptophan hydroxylase 1 (TPH1), which is regulator of tryptophane metabolism [20].

1. Kubo Y, Miyashita T, Murata Y
   Structural basis for a Ca2+-sensing function of the metabotropic glutamate receptors. Science (New York, N.Y.) 1998 Mar 13;279(5357):1722-5
2. Miyashita T, Kubo Y
   Extracellular Ca2+ sensitivity of mGluR1alpha associated with persistent glutamate response in transfected CHO cells. Receptors & channels 2000;7(1):25-40
3. Conn PJ, Pin JP
   Pharmacology and functions of metabotropic glutamate receptors. Annual review of pharmacology and toxicology 1997;37:205-37
4. Seeliger S, Vogl T, Engels IH, Schroder JM, Sorg C, Sunderkotter C, Roth J
   Expression of calcium-binding proteins MRP8 and MRP14 in inflammatory muscle diseases. The American journal of pathology 2003 Sep;163(3):947-56
5. Vogl T, Ludwig S, Goebeler M, Strey A, Thorey IS, Reichelt R, Foell D, Gerke V, Manitz MP, Nacken W, Werner S, Sorg C, Roth J
   MRP8 and MRP14 control microtubule reorganization during transendothelial migration of phagocytes. Blood 2004 Dec 15;104(13):4260-8
6. Pedrocchi M, Schafer BW, Durussel I, Cox JA, Heizmann CW
   Purification and characterization of the recombinant human calcium-binding S100 proteins CAPL and CACY. Biochemistry 1994 May 31;33(21):6732-8
7. Mbele GO, Deloulme JC, Gentil BJ, Delphin C, Ferro M, Garin J, Takahashi M, Baudier J
   The zinc- and calcium-binding S100B interacts and co-localizes with IQGAP1 during dynamic rearrangement of cell membranes. The Journal of biological chemistry 2002 Dec 20;277(51):49998-50007
8. Quednau BD, Nicoll DA, Philipson KD
   The sodium/calcium exchanger family-SLC8. Pflugers Archiv : European journal of physiology 2004 Feb;447(5):543-8
9. Hilge M, Aelen J, Vuister GW
   Ca2+ regulation in the Na+/Ca2+ exchanger involves two markedly different Ca2+ sensors. Molecular cell 2006 Apr 7;22(1):15-25
10. Iwamoto T, Shigekawa M
    Differential inhibition of Na+/Ca2+ exchanger isoforms by divalent cations and isothiourea derivative. The American journal of physiology 1998 Aug;275(2 Pt 1):C423-30
11. Uehara A, Iwamoto T, Kita S, Shioya T, Yasukochi M, Nakamura Y, Imanaga I
    Different cation sensitivities and binding site domains of Na+-Ca2+-K+ and Na+-Ca2+ exchangers. Journal of cellular physiology 2005 May;203(2):420-8
12. Aschner M, Dorman DC
    Manganese: pharmacokinetics and molecular mechanisms of brain uptake. Toxicological reviews 2006;25(3):147-54
13. Brazier MW, Davies P, Player E, Marken F, Viles JH, Brown DR
    Manganese binding to the prion protein. The Journal of biological chemistry 2008 May 9;283(19):12831-9
14. Kakuda S, Shiba T, Ishiguro M, Tagawa H, Oka S, Kajihara Y, Kawasaki T, Wakatsuki S, Kato R
    Structural basis for acceptor substrate recognition of a human glucuronyltransferase, GlcAT-P, an enzyme critical in the biosynthesis of the carbohydrate epitope HNK-1. The Journal of biological chemistry 2004 May 21;279(21):22693-703
15. Yang J, Goetz D, Li JY, Wang W, Mori K, Setlik D, Du T, Erdjument-Bromage H, Tempst P, Strong R, Barasch J
    An iron delivery pathway mediated by a lipocalin. Molecular cell 2002 Nov;10(5):1045-56
16. Beguin Y
    Soluble transferrin receptor for the evaluation of erythropoiesis and iron status. Clinica chimica acta; international journal of clinical chemistry 2003 Mar;329(1-2):9-22
17. Noppe W, Vanhoorelbeke K, Galaev IY, Mattiasson B, Deckmyn H
    A probe for capture and Fe3+-induced conformational change of lactoferrin selected from phage displayed peptide libraries. Journal of dairy science 2004 Oct;87(10):3247-55
18. Goodwill KE, Sabatier C, Stevens RC
    Crystal structure of tyrosine hydroxylase with bound cofactor analogue and iron at 2.3 A resolution: self-hydroxylation of Phe300 and the pterin-binding site. Biochemistry 1998 Sep 29;37(39):13437-45
19. Frantom PA, Seravalli J, Ragsdale SW, Fitzpatrick PF
    Reduction and oxidation of the active site iron in tyrosine hydroxylase: kinetics and specificity. Biochemistry 2006 Feb 21;45(7):2372-9
20. Hasegawa H, Oguro K, Naito Y, Ichiyama A
    Iron dependence of tryptophan hydroxylase activity in RBL2H3 cells and its manipulation by chelators. European journal of biochemistry / FEBS 1999 May;261(3):734-9