Ion channel activity of influenza A virus M2 protein: characterization of the amantadine block
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C Wang1, K Takeuchi, L H Pinto
1Howard Hughes Medical Institute, Northwestern University, Evanston, Illinois 60208-3500.
Abstract:
The influenza A virus M2 integral membrane protein has ion channel activity which can be blocked by the antiviral drug amantadine. The M2 protein transmembrane domain is highly conserved in amino acid sequence for all the human, swine, equine, and avian strains of influenza A virus, and thus, known amino acid differences could lead to altered properties of the M2 ion channel. We have expressed in oocytes of Xenopus laevis the M2 protein of human influenza virus A/Udorn/72 and the avian virus A/chicken/Germany/34 (fowl plague virus, Rostock) and derivatives of the Rostock ion channel altered in the presumed pore region. The pH of activation of the M2 ion channels and amantadine block of the M2 ion channels were investigated. The channels were found to be activated by pH in a similar manner but differed in their apparent Kis for amantadine block.
Insights
Influenza A virus M2 channels from human and avian strains show similar pH activation but differ in amantadine blocking. This finding is crucial for developing new antiviral drugs targeting influenza A M2 ion channels.
Area of Science:
- Virology
- Molecular Biology
- Pharmacology
Background:
- The M2 protein of influenza A virus functions as an ion channel.
- This ion channel activity is inhibited by the antiviral drug amantadine.
- The M2 protein's transmembrane domain is conserved across various influenza A strains, but sequence differences may alter channel properties.
Purpose of the Study:
- To investigate the functional differences between human and avian influenza A virus M2 ion channels.
- To compare the pH activation and amantadine sensitivity of these M2 ion channels.
Main Methods:
- Expression of M2 proteins from human (A/Udorn/72) and avian (A/chicken/Germany/34) influenza A viruses in Xenopus laevis oocytes.
- Electrophysiological recordings to assess ion channel activity.
- Determination of pH activation profiles and amantadine inhibition constants (Kis).
Main Results:
- Both human and avian M2 ion channels were activated by pH in a comparable manner.
- Significant differences were observed in the apparent inhibition constants (Kis) for amantadine block between the human and avian M2 channels.
- Derivatives of the avian Rostock channel with alterations in the presumed pore region were also studied.
Conclusions:
- Sequence variations in the M2 protein, particularly in the pore region, influence amantadine sensitivity.
- Understanding these differences is key for designing effective M2-targeting antiviral strategies against diverse influenza A strains.
- The study highlights the potential for strain-specific variations in drug efficacy.