Review

Purinergic Signalling

, Volume 1, Issue 4, pp 299-310

Open Access This content is freely available online to anyone, anywhere at any time.

Extracellular zinc and ATP-gated P2X receptor calcium entry channels: New zinc receptors as physiological sensors and therapeutic targets

  • Erik M. SchwiebertAffiliated withDepartment of Physiology and Biophysics, University of Alabama at BirminghamDepartment of Cell Biology, University of Alabama at BirminghamGregory Fleming James Cystic Fibrosis Research Center, University of Alabama at BirminghamRecessive Polycystic Kidney Disease Core Center, University of Alabama at BirminghamDepartment of Physiology and Biophysics, Center University of Alabama at Birmingham Email author 
  • , Lihua LiangAffiliated withDepartment of Physiology and Biophysics, University of Alabama at BirminghamGregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham
  • , Nai-Lin ChengAffiliated withDepartment of Physiology and Biophysics, University of Alabama at BirminghamGregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham
  • , Clintoria Richards WilliamsAffiliated withDepartment of Physiology and Biophysics, University of Alabama at Birmingham
  • , Dragos OlteanuAffiliated withDepartment of Physiology and Biophysics, University of Alabama at BirminghamRecessive Polycystic Kidney Disease Core Center, University of Alabama at Birmingham
  • , Elisabeth A. WeltyAffiliated withDepartment of Physiology and Biophysics, University of Alabama at BirminghamGregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham
  • , Akos ZsemberyAffiliated withDepartment of Physiology and Biophysics, University of Alabama at BirminghamGregory Fleming James Cystic Fibrosis Research Center, University of Alabama at BirminghamInstitute of Human Physiology and Clinical Experimental Research, Semmelweis University

Abstract

In this review, we focus on two attributes of P2X receptor channel function, one essential and one novel. First, we propose that P2X receptors are extracellular sensors as well as receptors and ion channels. In particular, the large extracellular domain (that comprises 70% of the molecular mass of the receptor channel protein) lends itself to be a cellular sensor. Moreover, its exquisite sensitivity to extracellular pH, ionic strength, and multiple ligands evokes the function of a sensor. Second, we propose that P2X receptors are extracellular zinc receptors as well as receptors for nucleotides. We provide novel data in multiple publications and illustrative data in this invited review to suggest that zinc triggers ATP-independent activation of P2X receptor channel function. In this light, P2X receptors are the cellular site of integration between autocrine and paracrine zinc signaling and autocrine and paracrine purinergic signaling. P2X receptors may sense changes in these ligands as well as in extracellular pH and ionic strength and transduce these sensations via calcium and/or sodium entry and changes in membrane potential.

Key words

β cells calcium cystic fibrosis diabetes epithelia P2X receptors polycystic kidney disease sensors zinc