Cross-Talk between Cholesterol, PIP2 and Caveolin in Regulating Kir2 Channels
| Autor: | Irena Levitan, Huazhi Han, Avia Rosenhouse-Dantsker, Frederick Sachs, Radhakrishnan Gnanasambandam |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Mutation Cholesterol Kinetic analysis Biophysics Gating Biology medicine.disease_cause Cell biology 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology chemistry Caveolae Caveolin cardiovascular system medicine lipids (amino acids peptides and proteins) Binding site Ion channel |
| Zdroj: | Biophysical Journal. 110:608a |
| ISSN: | 0006-3495 |
| DOI: | 10.1016/j.bpj.2015.11.3246 |
| Popis: | Multiple types of ion channels are regulated by two lipid modulators: phosphatidylinositol-4,5-bisphosphate (PIP2) and cholesterol, both modulators being enriched in caveolae. Our earlier studies identified cholesterol as a major negative regulator of Kir2 channels that are also well-known to be critically dependent on PIP2. Furthermore, it was proposed that cholesterol regulation of ion channels might be attributed to the disruption of their association with caveolin-1 and/or PIP2. In this study, we investigated the cross-talk between cholesterol, PIP2 and caveolin in the regulation of Kir2.1 channels. We show that cholesterol depletion strengthens the interaction between Kir2 channels and PIP2 and that a single-point mutation of Kir2.1 L222I that renders the channels cholesterol insensitive abrogates this effect. Furthermore, we present direct evidence that Kir2.1 is negatively regulated by Cav-1 and that Kir2.1-L222I mutation also abrogates the sensitivity of the channels to caveolin. Kinetic analysis of single-channel events also points to a common mechanism for cholesterol and Cav-1 regulation of the channels. However, neither Cav-1, nor intact caveolae are required for Kir2.1 channels to be cholesterol sensitive, thus challenging a general notion that cholesterol regulates ion channels by disruption of caveolae. Furthermore, we present first insights into the structural determinants of the cross-talk between the sensitivity of Kir2 channels to cholesterol, PIP2 and to caveolin: based on recent studies, we suggest that cholesterol, PIP2 and caveolin regulate the channels through distinct binding sites but that the signals generated by the binding of these modulators converge in regulating Kir2.1 gating. |
| Databáze: | OpenAIRE |
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