Expression Level of STIM Proteins Alter Electrophysiological Properties of Endogenous Calcium Channels

Abstract

Cell survival and normal cell function requires tight control of basal cytosolic Ca 2þ concentration. Fine-tuned regulation of cytosolic Ca 2þ concentrations is essential for various signaling pathways, controlling among others gene transcription, proliferation and cell migration. My studies focus especially on the understanding of the structural requirements triggering the co-regulation of the molecular key players of the CRAC channel STIM1 and Orai1 with small conductance Ca 2þ activated K þ channels (SK channels). Several publications have already provided evidence, that the interplay of Orai1 with SK3 is essential in the control of cancer cell growth, as their downregulation reduces cancer cell proliferation and migration. SK3 channels are activated by intracellular Ca 2þ in the range of 0.1-0.25 mM. I discovered in electrophysiological studies in the absence of intracellular Ca 2þ that a co-expression of Orai1 and SK3 in HEK cells initiates the activation of SK3-like currents, in contrast to SK3 alone which remains inactive under these conditions. A combined approach of Ca 2þ imaging, electrophysiological and fluorescence microscopy will uncover the so far unresolved molecular key determinants regulating the interplay and co-localization of the channels, potentially providing more specific target sites for cancer treatment. (Supported by Austrian Science Fund FWF P25210 and P27641 to I.D. and P27263 to C.R.).