A new regulation mechanism for KCNN4, the Ca2+-dependent K+ channel, by molecular interactions with the Ca2+pump PMCA4b
Year: 2024
Type: article
Abstract: KCNN4, a Ca 2+ -activated K + channel, is involved in various physiological and pathological processes. It is essential for epithelial transport, immune system, and other physiological mechanisms, but its activation is also involved in cancer pathophysiology as well as red blood cell (RBC) disorders. The activation of KCNN4 in RBC leads to loss of KCl and water, a mechanism known as the "Gardos effect" described 70 years ago. This Ca 2+ -induced dehydration is irreversible in human RBC and must be tightly controlled to prevent not only hemolysis but also alterations in RBC rheological properties. In this study, we have investigated the regulation of KCNN4 activity after changes in RBC Ca 2+ concentration. Using electrophysiology, immunoprecipitation, and proximity ligation assay in human embryonic kidney 293–transfected cells, K562 cells, or RBCs, we have found that KCNN4 and the Ca 2+ pump PMCA4b (plasma membrane calcium-transporting ATPase 4b) interact tightly with each other, such that the C-terminal domain of PMCA4b regulates KCNN4 activity, independently of the Ca 2+ extrusion activity of the pump. This regulation was not restricted to KCNN4: the small-conductance Ca 2+ -activated K + channel KCNN2 was similarly regulated by the calcium pump. We propose a new mechanism that could control KCNN4 activity by a molecular inhibitory interaction with PMCA4b. It is suggested that this mechanism could attenuate erythrocyte dehydration in response to an increase in intracellular Ca 2+ .
Source: Journal of Biological Chemistry
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,800
OpenAlex ID: W4405674499