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1.A.15 The Non-selective Cation Channel-2 (NSCC2) Family

Members of the NSCC2 family have been sequenced from various yeast, fungal and animals species including Saccharomyces cerevisiae, Drosophila melanogaster and Homo sapiens. These proteins are the Sec62 proteins, believed to be associated with the Sec61 and Sec63 constituents of the general protein secretory systems of yeast microsomes. They are also the non-selective cation (NS) channels of the mammalian cytoplasmic membrane. The yeast Sec62 protein has been shown to be essential for cell growth. The mammalian NS channel proteins have been implicated in platelet derived growth factor (PDGF)-dependent single channel current in fibroblasts. These channels are essentially closed in serum deprived tissue-culture cells and are specifically opened by exposure to PDGF. The channels are reported to exhibit equal selectivity for Na+ , K+ and Cs+ with low permeability to Ca2+ , and no permeability to anions. Channel open probability is voltage- and cytoplasmic Ca2+-independent.

Sequenced NSCC2 family proteins are 283-402 amino acyl residues in length and exhibit two putative transmembrane α-helical spanners (TMSs). The S. cerevisiae protein, of 283 amino acyl residues, has cytoplasmic N- and C-termini with two putative TMSs at positions 159-178 and 193-213. The C-terminal 25 residues are rich in arginine and lysine. The animal proteins are about 30% identical to the yeast proteins. It is not known if the yeast proteins can function as ion channels or if the animal proteins facilitate protein secretion. These proteins have been reported to be present in both endoplasmic reticular and cytoplasmic membranes. In spite of their observed low Ca2+  conductance, the mammalian NSCC2 proteins are irreversibly activated by maitotoxin (MTX). MTX may also form pores at higher concentrations (Egido et al., 2008). NSCC2 channels are believed to provide entry pathways in response to growth factors.

The generalized transport reaction catalyzed by members of the NSCC2 family is:

Cation (out) cation (in)

References associated with 1.A.15 family:

Egido, W., V. Castrejón, B. Antón, and M. Martínez. (2008). Maitotoxin induces two dose-dependent conductances in Xenopus oocytes. Comparison with nystatin effects as a pore inductor. Toxicon. 51: 797-812. 18255116 18255116 18255116
Bihler, H., C.L. Slayman, and A. Bertl. (1998). NSC1: a novel high-current inward rectifier for cations in the plasma membrane of Saccharomyces cerevisiae. FEBS Lett. 432: 59-64. 9710251 9710251
Estacion, M., H. B. Nguyen and J.J. Gargus (1996). Calcium is permeable through a maitotoxin-activated nonselective cation channel in mouse L cells. Am. J. Physiol. 270: C1145-C1152. 8928742
Fantino, E., D. Church, U. Bengtsson and J.J. Gargus (1997). Mammalian gene encoding growth factor-activated cation channel is homologue to yeast microsomal protein SEC62 and maps to human chromosome 3. J. Gen. Physiol. 110: 44a.
Frace, A.M. and J.J. Gargus (1989). Activation of single-channel currents in mouse fibroblasts by platelet-derived growth factor. Proc. Natl. Acad. Sci. USA 86: 2511-2515. 2467305
Gargus, J.J., A.M. Frace and F. Jung (1993). The role of a PDGF-activated nonselective cation channel in the proliferative response. In "Nonselective cation channels: pharmacology, physiology and biophysics" (D. Siemen and J. Hescheler, eds.), Birkhäuser Verlag, Basel, Switzerland, pp. 289-295. 7505659
Jung, F., S. Selvaraj and J.J. Gargus (1992). Blockers of platelet-derived growth factor-activated nonselective cation channel inhibit cell proliferation. Am. J. Physiol. 262: C1464-C1470. 1377445
Lakkaraju, A.K., R. Thankappan, C. Mary, J.L. Garrison, J. Taunton, and K. Strub. (2012). Efficient secretion of small proteins in mammalian cells relies on Sec62-dependent posttranslational translocation. Mol. Biol. Cell 23: 2712-2722. 22648169
Lyman, S.K. and R. Schekman. (1997). Binding of secretory precursor polypeptides to a translocon subcomplex is regulated by BiP. Cell 88: 85-96. 9019409