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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.