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Molecular Medicine

, Volume 21, Issue 1, pp 323–336 | Cite as

A Human-Specific α7-Nicotinic Acetylcholine Receptor Gene in Human Leukocytes: Identification, Regulation and the Consequences of CHRFAM7A Expression

  • Todd W. Costantini
  • Xitong Dang
  • Maryana V. Yurchyshyna
  • Raul Coimbra
  • Brian P. Eliceiri
  • Andrew Baird
Research Article

Abstract

The human genome contains a variant form of the α7-nicotinic acetylcholine receptor (α7nAChR) gene that is uniquely human. This CHRFAM7A gene arose during human speciation and recent data suggests that its expression alters ligand tropism of the normally homopentameric human α7-AChR ligand-gated cell surface ion channel that is found on the surface of many different cell types. To understand its possible significance in regulating inflammation in humans, we investigated its expression in normal human leukocytes and leukocyte cell lines, compared CHRFAM7A expression to that of the CHRNA7 gene, mapped its promoter and characterized the effects of stable CHRFAM7A overexpression. We report here that CHRFAM7A is highly expressed in human leukocytes but that the levels of both CHRFAM7A and CHRNA7 mRNAs were independent and varied widely. To this end, mapping of the CHRFAM7A promoter in its 5′-untranslated region (UTR) identified a unique 1-kb sequence that independently regulates CHRFAM7A gene expression. Because overexpression of CHRFAM7A in THP1 cells altered the cell phenotype and modified the expression of genes associated with focal adhesion (for example, FAK, P13K, Akt, rho, GEF, Elk1, CycD), leukocyte transepithelial migration (Nox, ITG, MMPs, PKC) and cancer (kit, kitL, ras, cFos cyclinD1, Frizzled and GPCR), we conclude that CHRFAM7A is biologically active. Most surprisingly however, stable CHRFAM7A overexpression in THP1 cells upregulated CHRNA7, which, in turn, led to increased binding of the specific α7nAChR ligand, bungarotoxin, on the THP1 cell surface. Taken together, these data confirm the close association between CHRFAM7A and CHRNA7 expression, establish a biological consequence to CHRFAM7A expression in human leukocytes and support the possibility that this human-specific gene might contribute to, and/or gauge, a human-specific response to inflammation.

Notes

Acknowledgments

The authors wish to thank Emelie Amburn, Annemarie Hageny and James Putnam for their expert technical assistance and support from the National Institutes of Health (CA170140) and a Department of Defense Grant administered by the American Burn Association (W81XWH-10-1-0527). The research presented here originated with seed funding from an NIH P20 Center for Exploratory Wound Healing Research (NIGM78421).

Supplementary material

10020_2015_2101323_MOESM1_ESM.pdf (7 mb)
Supplementary material, approximately 7.01 MB.

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Authors and Affiliations

  • Todd W. Costantini
    • 1
  • Xitong Dang
    • 1
    • 2
  • Maryana V. Yurchyshyna
    • 1
  • Raul Coimbra
    • 1
  • Brian P. Eliceiri
    • 1
  • Andrew Baird
    • 1
  1. 1.Division of Trauma, Surgical Care, Burns, and Acute Care Surgery, Department of SurgeryUniversity of California San Diego Health SciencesSan DiegoUSA
  2. 2.Cardiovascular Research CenterLuzhou Medical CollegeLuzhou, SichuanChina

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