Marquee Middle Image

Faculty Profile

Myles Akabas, M.D., Ph.D.

Dr. Myles Akabas
 

Professional Interests

MALARIA PARASITE PHYSIOLOGY AND MECHANISMS OF NUCLEOSIDE AND DRUG TRANSPORT

Malaria is a major public health problem affecting large areas of the world, killing several million people, mostly children and pregnant woman, each year. Malaria is caused by unicellular parasites from the Plasmodium species that grow inside erythrocytes. Plasmodium falciparum causes the most lethal form of malaria. Plasmodium spp. parasites are purine auxotrophs and require an exogenous source of purines to survive. They import purine precursors from the host erythrocyte via equilibrative nucleoside transporters (ENTs). Knockout of PfENT1 is lethal at purine concentrations found in human plasma. This suggests that PfENT1 inhibitors might kill parasites and represent a novel drug target for antimalarial drugs. We seek to characterize the purine nucleoside transporters and identify inhibitors as potential antimalarial drugs. We have developed a yeast-based high throughput screen to identify PfENT1 inhibitors. We have screened a 60,000 compound library and identified 171 hits. The nine best hits block PfENT1 and kill P. falciparum parasites in culture. We are characterizing the hits and exploring the SAR for the compounds to identify more potent derivatives. Additional work is focused on testing the hits in a mouse malaria model and against P. vivax ENT1.


NEUROTRANSMITTER-GATED ION CHANNELS: STRUCTURE, FUNCTION AND PHARMACOLOGY

Neurotransmitter-gated ion channels are essential components in synaptic transmission. They are a major target for drugs used clinically including general anesthetics. Our work focuses on the GABAA receptor, the major post-synaptic inhibitory neurotransmitter receptor in brain. It is the target for drugs used clinically in the treatment of anxiety and epilepsy, and for general anesthesia. GABAA receptors are members of a gene superfamily that includes receptors for glycine, acetylcholine, and serotonin. We seek to provide a molecular understanding of the structural bases for receptor function, modulation by drugs and cellular trafficking. This would provide a basis for rational drug design and an understanding of the molecular mechanisms by which general anesthetics function. We use a combination of techniques including site-directed mutagenesis, heterologous expression, covalent chemical modification and electrophysiology. These studies have identified the residues lining the channel, the location of channel blocker binding sites and identified conformational changes occurring during channel gating and modulation by drugs including valium and propofol.

 

Selected Publications

  1. Brass, L.F., Akabas, M.H., Burnley, L.D., Engman, D.M., Wiley, C.A., Andersen, O.S. (2010) An analysis of career choices made by graduates of 24 MD-PhD programs. Acad. Med. 85:692-701.
  2. Riegelhaupt, P.M.*, Frame, I.J.* and Akabas, M.H. (2010) Transmembrane segment 11 appears to line the purine permeation pathway of the Plasmodium falciparum equilibrative nucleoside transporter 1 (PfENT1). J. Biol. Chem. 285:17001-10. (*contributed equally)
  3. Parikh, R., Bali, M., and Akabas, M.H. (2011) Structure of M2 transmembrane segment of GLIC, a prokaryotic Cys-loop receptor homologue from Gloeobacter violaceus, probed by substituted cysteine accessibility. J. Biol. Chem. 286:14098-14109.
  4. McKinnon, N.*, Reeves, D.C.* and Akabas, M.H. (2011) 5-HT3 receptor ion size selectivity is a property of the transmembrane channel not the portals to the cytoplasmic vestibule. J. Gen. Physiol. 138:453-466. (*contributed equally)
  5. Collins, B., Kane, E.A., Reeves, D.C., Akabas, M.H. and Blau, J. (2012) Decoding a circadian neural circuit. Neuron 74:706-718.
  6. Frame, I.J., Merino, E.F., Schramm, V.L., Cassera, M.B., and Akabas, M.H. (2012) Malaria parasite Type 4 equilibrative nucleoside transporters (ENT4) are purine transporters with distinct substrate specificity. Biochem. J. 446:179-90.
  7. Bali, M. and Akabas, M.H. (2012) Gating induced conformational rearrangement of the GABAA receptor beta-alpha subunit interface in the membrane-spanning domain. J. Biol. Chem. 287:27762-70.
  8. Akabas, M.H. (2013) Using molecular dynamics to elucidate the structural basis for function in pLGICs. Proc. Natl. Acad. Sci. USA 110:16700-16701.
 

More Information About Dr. Myles Akabas

Akabas Lab Web Site

Material in this section is provided by individual faculty members who are solely responsible for its accuracy and content.

Contact

Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
1300 Morris Park Avenue
Ullmann Building, Room 209
Bronx, NY 10461

Tel: 718.430.3360
Fax: 718.430.8819
myles.akabas@einstein.yu.edu

 
Pubmed Search
Collexis Research Profiles
Einstein Research Profiles (ERP) is one of the innovative technologies to create collaborative bridges within and across the entire bench-to-bedside-to-population spectrum of research. The ERP website has been developed in partnership with Collexis to give investigators easy access to PubMed publications, coauthor networks, information about NIH grants, and research networks.