Annexins sense changes in intracellular pH during hypoxia

Area of Science:

• Cell Biology
• Physiology
• Biochemistry

Background:

• Intracellular pH (pH(i)) is a critical physiological parameter, significantly decreasing during hypoxia and ischemia.
• pH(i) influences cellular processes like proliferation and apoptosis via ion transport systems.
• Annexins are proteins known for calcium-dependent membrane interactions, with some also showing pH-dependent, calcium-independent binding.

Purpose of the Study:

• To investigate the in vivo influence of intracellular pH on the membrane association of human annexins.
• To characterize the pH-dependent membrane interactions of specific annexins in smooth muscle and HEK-293 cells.
• To determine the role of annexin A2 dimerization in pH-mediated membrane binding.

Main Methods:

• Utilized fluorescently tagged human annexins (A1, A2, A4, A5, A6) for in vivo studies.
• Employed biochemical assays and immunofluorescence microscopy to analyze endogenous annexins in smooth muscle and HEK-293 cells.
• Investigated recombinant annexin A2-S100A10 and annexin A6 interactions with the plasma membrane under hypoxic conditions.

Main Results:

• Hypoxia promotes the plasma membrane interaction of recombinant annexin A2-S100A10 and annexin A6.
• Annexin A6 and the annexin A2-S100A10 heterotetramer, but not A1, A4, or A5, bind the plasma membrane independently of Ca2+ at pH 6.2 and 6.6.
• Dimerization of annexin A2 within the A2-S100A10 complex is crucial for this pH-dependent membrane interaction.

Conclusions:

• Annexin A6 and the A2-S100A10 complex exhibit pH-dependent, calcium-independent membrane association at acidic intracellular pH.
• The dimerization of annexin A2 is essential for the pH-sensitive membrane targeting of the A2-S100A10 complex.
• These pH-induced annexin-membrane interactions may influence their roles in membrane organization and ion channel modulation.