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Correspondence: Toni schneider institute of neurophysiology, University of Cologne, Robert-Koch-str 39, D-50931 Köln, germany Tel +49 22 1478 6946 Fax +49 22 1478 6965 email toni.schneider@uni-koeln.de Abstract: Cytosolic segments of membrane-bound voltage-gated Ca2+ channels are targets for specific signaling complexes which regulate important physiological processes via soluble protein interaction partners. The molecular chaperone heat shock 70 kDa protein 1A (Hsp70) was identified as a binding partner for the II-III loop of the ion-conducting α1 subunit of the E-type voltage-gated Ca2+ channel (Ca v 2.3) by mass spectrometry. To substantiate this finding further and to test its functional significance in vivo, two approaches were chosen. HEK-293 cells stably transfected with Ca v 2.3 were treated with a cell-permeable form of Hsp70 (Tat-Hsp70, Tat being a protein transduction domain of the “transactivator of transcription” from the human immunodeficiency virus) and analyzed by whole cell Ca2+ current recordings. Tat-Hsp70 1 μM shifted the voltage-dependence of the inward currents to more hyperpolarized potentials. Further, the inactivation of transient inward Ca2+ currents carried by Ca v 2.3 was slowed down. After isolation of hippocampal microsomes from control mice by ultracentrifugation, about 0.09% of total Hsp70 protein was bound to the microsomal fraction. Hsp70 binding to membranes was increased when kainate 20 mg/kg was injected intraperitoneally at concentrations which induced seizures and neurodegeneration in control mice. In Ca v 2.3-deficient mice, only mild seizures were observed after kainate injection, with no hippocampal neurodegeneration. Moreover, we observed no increase in Hsp70 binding to the membrane fraction of the isolated hippocampal microsomes, indicating that Hsp70 may be an important intermediate signaling partner for hippocampal neurodegeneration in Ca v 2.3(+/+) mice. Our results suggest that the Ca v 2.3 interaction partner, Hsp70, and its membrane association are important for understanding the molecular events in kainate-induced hippocampal neurodegeneration.

Interaction of recombinant and native Cav2.3 E-/R-type voltage-gated Ca2+ channels with the molecular chaperone Hsp70