HIV-gp120 activates large-conductance apamin-sensitive potassium channels in rat astrocytes.
Central nervous system (CNS) involvement usually occurs in individuals infected with human immunodeficiency virus type 1 (HIV-1). Evidence is now accumulating that neurons and astrocytes may be functionally compromised by exposure to viral components or cellular factors released from HIV-1-infected macrophages and/or microglia. We have previously reported that the HIV coat protein gp120 stimulates Na+/H+ exchange in primary cultured rat astrocytes, which, ultimately, results in the activation of a K+ conductance. In this report we characterize the electrophysiological and biophysical properties of the channels responsible for the gp120-induced increase in K+ conductance. These K+ channels had a relatively large unitary conductance (147 pS), were not gated by voltage, were sensitive to changes in H+ concentration at their cytosolic face, were specifically inhibited by apamin, and were insensitive to charybdotoxin and tetraethylammonium. The activation of these channels by gp120 is referable to cellular alkalinization subsequent to Na+/H+ exchange stimulation; gp120 failed to activate these K+ channels in the absence of external Na+ or in the presence of amiloride, an inhibitor of Na+/H+ exchange. Subsequent K+ loss from the astrocyte into the restricted extracellular space surrounding neurons can then lead to neuronal depolarization, activation of voltage-sensitive Ca2+ channels, and, eventually, cell death. Thus abnormal activation of astrocyte K+ channels by gp120 may contribute to the CNS pathophysiology associated with HIV-1 infection.
Bubien
J K
JK
Department of Medicine, University of Alabama at Birmingham 35294, USA.
Benveniste
E N
EN
Benos
D J
DJ
D015526:AIDS Dementia Complex / Q000503:physiopathology; D000266:Adenylyl Imidodiphosphate / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001030:Apamin / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000502:physiology*; D004553:Electric Conductivity; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology*; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology
D015699:HIV Envelope Protein gp120; D015221:Potassium Channels; D011994:Recombinant Proteins; D001030:Apamin; D000266:Adenylyl Imidodiphosphate