16 The Influenza A Virus M2 Ion Channel Protein and Its Role in the Influenza Virus Life Cycle

Abstract

The influenza virus M2 protein has an ion channel activity that permits ions to enter the virion during uncoating and also acts to modulate the pH of intracellular compartments. In this review, we discuss the structure of the M2 protein; the observations concerning the effect of the antiviral drug amantadine on influenza virus replication which led to the notion that the M2 protein could affect intracellular pH; the direct evidence indicating that the M2 protein has an ion channel activity that is blocked by amantadine; and properties of the M2 protein’s ion channel activity.

STRUCTURE OF THE M2 PROTEIN
The influenza A virus envelope contains three integral membrane proteins, hemagglutinin (HA), neuraminidase (NA), and the M2 protein. Contained inside the viral envelope are the ribonucleoprotein (RNP) structures, which consist of one of the eight genomic RNA segments encapsidated with nucleocapsid protein (NP) and the associated RNA transcriptase protein complex. The influenza virus membrane protein (M1) is a peripheral membrane protein that is thought to associate with both the RNPs and the lipid bilayer (for review, see Lamb 1989). The M2 integral membrane protein (97 amino acids) is encoded by a spliced mRNA derived from genome RNA segment 7 (Lamb and Choppin 1981; Lamb et al. 1981). The M2 protein is abundantly expressed at the plasma membrane of virus-infected cells but is greatly underrepresented in virions, as only a few (on average 20–60) molecules are incorporated into virus particles (Lamb et al. 1985; Zebedee et al. 1985; Zebedee and Lamb...