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Hamid Akbarali, Ph.D. Hamid Akbarali, Ph.D.
Professor
1112 East Clay Street
McGuire Hall Room 317
P.O. Box 980524
Richmond, Virginia 23298
Phone: (804) 828-9688
E-mail: hiakbarali@vcu.edu
Publications: selected | PubMed
Webpage: http://www.vpens.vcu.edu
 

Education: Memorial University of Newfoundland, St. John’s, Canada 1988

Research interests:

The overall focus of our research is on the physiology and pharmacology of the gastrointestinal system. The main areas of research are:
      1) Characterization of altered ion channel function in colonic inflammation
      2) Opioid Bowel Dysfunction
      3) Ion channels in visceral pain

Ion channels in gastrointestinal smooth muscle and inflammation:
Ion channels are integral membrane proteins that control the excitability of cells and are a major mechanism by which external signals are transduced to the cell. Mutations in ion channels manifest in several diseases (channelopathies) due to functional abnormality of cell excitability. In our laboratory we are interested in characterizing the cellular basis of electrical excitability of smooth muscle from gene expression to electrical gating of ion channels. The aim of our research is to identify the channel proteins that determine the excitability of gastrointestinal smooth muscle and how the various ion channels orchestrate the response to neurotransmitters and hormones.  We are particularly focused on changes in ion channel function associated with colonic inflammation.

Recent studies in our laboratory have focused on down regulation of calcium channels in colonic inflammation.  We have developed a working model that demonstrates inflammation-induced increase in reactive nitrogen species, RNS, results in the nitration of tyrosine residues within the carboxy terminus of the smooth muscle calcium channel.  The nitration of specific tyrosine residues prevents basal regulation by the tyrosine kinase, c-src kinase, leading to decreased calcium currents.  The main focus is to determine the mechanism by which c-src kinase regulates calcium channels, identification of the docking sites for src kinase, the process of recovery from nitration and its effect on muscle contraction.  We use several approaches in our studies including whole cell and single channel patch clamp techniques, real time PCR, fluorescence resonance energy transfer (FRET), confocal microscopy, site-directed mutagenesis and gene manipulation.

Opioid induced bowel dysfunction:
Morphine, an alkaloid derived from the opium poppy papaver somniferum, is one of the most frequently prescribed drugs for the treatment of moderate to severe pain.  A major side-effect of morphine is constipation.  Repeated administration of morphine results in the development of tolerance to its analgesic effects, however, constipation remains resistant to tolerance development.  Our studies are focused on determining the basis of morphine’s effect in the colon and the mechanisms associated with the development of tolerance in the CNS and gastrointestinal tract.  These studies in collaboration with Dr William Dewey, utilize several approaches including defining opioid receptors in the enteric neurons, molecular basis for tolerance development in the ileum and colon, and studies in chronic morphine treated mice models.

Ion channels in visceral pain:
Chronic pelvic pain is a common symptom associated with Irritable Bowel Syndrome (IBS), Interstitial Cystitis (IC) and Inflammatory Bowel Diseases (IBS).  We have identified changes in ion channel function within cell bodies of sensory neurons (dorsal root ganglia) projecting from the colon following colonic inflammation that may be responsible for the cross-sensitization between the bladder and colon.  In collaboration with the members of VCU Program in Enteric Neuromuscular Sciences (VPENS) and the Department of Pharmacology, we are pursuing altered channel function function in:
    a) cross-sensitization pathways between the bladder and colon,
    b) effects of neurotrophins on ion channel function,
    c) effects of nicotine and morphine in DRG during colonic inflammation.

Selected publications:

Akbarali HI, Hawkins EG, Ross GR and Kang M. (2010) Ion channel remodeling in gastrointestinal inflammation (invited review) Neurogastroenterol Motil. 22: 1045-55.

Abdrakhmanova GR, Alsharari S, Kang M, Damaj MI, and Akbarali HI. (2010) {alpha}7 nAChR-mediated suppression of hyperexcitability of colonic dorsal root ganglia neurons in experimental colitis. Am J Physiol. 299:G761-8.

Ross GR, Kang M and Akbarali HI. (2010) Colonic inflammation alters src-kinase gating properties of single Ca2+ channels via tyrosine nitration. Am J Physiol. 298: G976-84.

Kang M, Ross GR and Akbarali HI. (2010) The effect of tyrosine nitration of L-type Ca2+ channel on excitation-transcription coupling in colonic inflammation. Br J Pharmacol. 159: 1226-1235.

Kang M and Akbarali HI (2008) Denitration of L-type Calcium Channel. FEBS Lett. 582: 3033-6.

Ross GR, Gabra BH, Dewey WL and Akbarali HI. (2008) Morphine tolerance in the mouse ileum and colon. J Pharmacol Exp Ther. 327:561-72.

Kang M, Ross GR and Akbarali HI. (2007) C-terminal association of human smooth muscle calcium channel Cav1.2b with c-src kinase protein binding domains: Effect of nitrotyrosylation. Amer J Physiol (Cell) 293:C1983-90.

Ross GR, Kang M, Malykhina AP, Shirwany N, Drozd M and Akbarali HI. (2007) Nitrotyrosylation of calcium channels prevents c-src kinase regulation of colonic smooth muscle contractility in experimental colitis. J Pharmacol Exp Ther 322:948-56.

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