CONTACT INFORMATION http://www.loyola.org
Saverio Gentile
Ph.D.
  • Assistant Professor
  • Molecular Pharmacology and Therapeutics
Research Summary

Hormonal-dependent regulation of ion channels in physiological and
pathological conditions

Both steroid hormones and ion channels are known to play fundamental roles in the regulation of many varied physiological events. But until recently it was not appreciated that these two biological pathways functionally intersect. In this regard, evidence has recently emerged linking the non-genomic action of steroid hormones to the regulation of ion channel activity. Exposure of cells to certain steroid hormones has been shown to stimulate the activity of cellular protein kinase signaling pathways that in turn have been shown to phosphorylate ion channels resulting in a modification of their biological activity. In fact, we have recently found that several disease-associated mutations in different ion channels can actually create or disrupt consensus sites for protein kinases (ion channel phosphorylopathies). Accordingly, we predict that the hormone-induced alteration in ion channel phosphorylation may play a major role in affecting the activity and physiological function of ion channels in vivo.

Recently, potassium ion channels have been found to play an important role in promoting tumor progression in a variety of different cell types. However, very little is known regarding the mechanisms linking these channels to tumorigenesis. Consequently, my lab is interested in elucidating and understanding the biochemical signaling pathways that link the activity of the hERG1 pottasium channel to cancer cell proliferation and increased tumourigenic potentiall, and the role that hormonal regulation may play in these events. We have established a line of research in which we are investigating the role and function of the hERG1 ion channel in breast cancer. Our pioneering experiments are revealing that the hERG1 channel appears to be involved in promoting cell cycle progression and protecting cells from apoptosis and senescence.

Untangling the mechanism linking hormones to ion channels will offer
new opportunities to extend our knowledge of the role of ion channels in physiological and pathological conditions.

Publications

Potassium channel activation inhibits proliferation of breast cancer cells by activating a senescence programLansu,K.; Gentile,S.Cell death & disease 2013 ;4( ):e652

Social networking among voltage-activated potassium channelsBrueggemann,L. I.; Gentile,S.; Byron,K. L.Progress in molecular biology and translational science 2013 ;117( ):269-302

Long QT2 mutation on the Kv11.1 ion channel inhibits current activity by ablating a protein kinase Calpha consensus siteDonovan,A. J.; Lansu,K.; Williams,J. G.; Denning,M. F.; Gentile,S.Molecular pharmacology 2012 ;82(3):428-437

The human ERG1 channel polymorphism, K897T, creates a phosphorylation site that inhibits channel activity.Gentile,S.; Martin,N.; Scappini,E.; Williams,J.; Erxleben,C.; Armstrong,D. L.Proceedings of the National Academy of Sciences of the United States of America 2008 ;105(38):14704-14708

Rapid signaling at the plasma membrane by a nuclear receptor for thyroid hormone.Storey,N. M.; Gentile,S.; Ullah,H.; Russo,A.; Muessel,M.; Erxleben,C.; Armstrong,D. L.Proceedings of the National Academy of Sciences of the United States of America 2006 ;103(13):5197-5201

Rac GTPase signaling through the PP5 protein phosphatase.Gentile,S.; Darden,T.; Erxleben,C.; Romeo,C.; Russo,A.; Martin,N.; Rossie,S.; Armstrong,D. L.Proceedings of the National Academy of Sciences of the United States of America 2006 ;103(13):5202-5206

Cyclosporin and Timothy syndrome increase mode 2 gating of CaV1.2 calcium channels through aberrant phosphorylation of S6 helices.Erxleben,C.; Liao,Y.; Gentile,S.; Chin,D.; Gomez-Alegria,C.; Mori,Y.; Birnbaumer,L.; Armstrong,D. L.Proceedings of the National Academy of Sciences of the United States of America 2006 ;103(10):3932-3937