DEPARTMENT OF NEUROBIOLOGY

Research Summary

Influenza Virus Ion Channel

Influenza continues to kill more people in the developed world than AIDS. There are only two inhibitors of the virus that work for people who are already infected, and one of them, amantadine, works by inhibiting the ion channel contained in the virus particle. We study this ion channel because of its importance in the virus and because it serves as a simple model of ion channels in general.

Gene Discovery Project

By mutagenizing mice and screening them for specific functional defects, scientists have been able to discover genes that are involved in the various important biological processes and to create models for important human diseases. An example of one important process is the circadian clock, and the essential Clock gene of the mouse was discovered in our department using this approach. My lab is using this process to identify mutations affecting blindness and asthma.

Selected Publications

• Rossman JS, Jing X, Leser GP, Balannik V, Pinto LH, Lamb RA. (2010). Influenza virus m2 ion channel protein is necessary for filamentous virion formation. J Virol, May;84(10):5078-88.
• Balannik V, Carnevale V, Fiorin G, Levine BG, Lamb RA, Klein ML, Degrado WF, Pinto LH. (2010). Functional studies and modeling of pore-lining residue mutants of the influenza a virus M2 ion channel. Biochemistry, Feb 2;49(4):696-708.
• Balannik V, Obrdlik P, Inayat S, Steensen C, Wang J, Rausch JM, DeGrado WF, Kelety B, Pinto LH. (2009). Solid-supported membrane technology for the investigation of the influenza A virus M2 channel activity. Pflugers Arch, Mar;459(4):593-605.
• Balannik V, Wang J, Ohigashi Y, Jing X, Magavern E, Lamb RA, Degrado WF, Pinto LH. (2009). Design and pharmacological characterization of inhibitors of amantadine-resistant mutants of the M2 ion channel of influenza A virus. Biochemistry, Dec 22;48(50):11872-82.
• Ohigashi Y, Ma C, Jing X, Balannick V, Pinto LH, Lamb RA. (2009). An amantadine-sensitive chimeric BM2 ion channel of influenza B virus has implications for the mechanism of drug inhibition. Proc Natl Acad Sci USA, Nov 3;106(44):18775-9.
• Ma C, Polishchuk AL, Ohigashi Y, Stouffer AL, Schön A, Magavern E, Jing X, Lear JD, Freire E, Lamb RA, DeGrado WF, Pinto LH. (2009). Identification of the functional core of the influenza A virus A/M2 proton-selective ion channel. Proc Natl Acad Sci USA, Jul 28;106(30):12283-8.
• Wang J, Cady SD, Balannik V, Pinto LH, DeGrado WF, Hong M. (2009). Discovery of spiro-piperidine inhibitors and their modulation of the dynamics of the M2 proton channel from influenza A virus. J Am Chem Soc, Jun 17;131(23):8066-76.
• Nguyen PA, Soto CS, Polishchuk A, Caputo GA, Tatko CD, Ma C, Ohigashi Y, Pinto LH, DeGrado WF, Howard KP. (2008). pH-Induced conformational change of the influenza M2 protein C-terminal domain. Biochemistry, 47(38):9934-6.
• Maddox DM, Vessey KA, Yarbrough GL, Invergo BM, Cantrell DR, Inayat S, Balannik V, Hicks WL, Hawes NL, Byers S, Smith RS, Hurd R, Howell D, Gregg RG, Chang B, Naggert JK, Troy JB, Pinto LH, Nishina PM, McCall MA. (2008). Allelic variance between GRM6 mutants, Grm6nob3 and Grm6nob4 results in differences in retinal ganglion cell visual responses. J Physiol, 586 (Pt 18): 4409-24.
• Jing X, Ma C, Ohigashi Y, Oliveira FA, Jardetzky TS, Pinto LH, Lamb RA. (2008). Functional studies indicate amantadine binds to the pore of the influenza A virus M2 proton-selective ion channel. Proc Natl Acad Sci U S A, 105(31): 10967-72.
• Stouffer AL, Ma C, Cristian L, Ohigashi Y, Lamb RA, Lear JD, Pinto LH, DeGrado WF. (2008). The interplay of functional tuning, drug resistance, and thermodynamic stability in the evolution of the M2 proton channel from the influenza A virus. Structure, 16(7):1067-76.
• Ma C, Soto CS, Ohigashi Y, Taylor A, Bournas V, Glawe B, Udo MK, Degrado WF, Lamb RA, Pinto LH. (2008). Identification of the pore-lining residues of the BM2 ion channel protein of influenza B virus. J Biol Chem, 283(23):15921-31.
• PubMed