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Modulation of Mammalian Inositol 1,4,5-Trisphosphate Receptor Isoforms by Calcium: A Role of Calcium Sensor Region

Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390

Correspondence: Address reprint requests to Dr. Ilya Bezprozvanny, Dept. of Physiology, K4.112 UT Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-9040. Tel.: 214-648-6737; Fax: 214-648-2974; E-mail: ilya.bezprozvanny{at}utsouthwestern.edu.

In the accompanying article, we compared main functional properties of the three mammalian inositol 1,4,5-trisphosphate receptors (InsP₃R) isoforms. In this article we focused on modulation of mammalian InsP₃R isoforms by cytosolic Ca²⁺. We found that: 1), when recorded in the presence of 2 µM InsP₃ and 0.5 mM ATP all three mammalian InsP₃R isoforms display bell-shaped Ca²⁺ dependence in physiological range of Ca²⁺ concentrations (pCa 8–5); 2), in the same experimental conditions InsP₃R3 is most sensitive to modulation by Ca²⁺ (peak at 107 nM Ca²⁺), followed by InsP₃R2 (peak at 154 nM Ca²⁺), and then by InsP₃R1 (peak at 257 nM Ca²⁺); 3), increase in ATP concentration to 5 mM had no significant effect of Ca²⁺ dependence of InsP₃R1 and InsP₃R2; 4), increase in ATP concentration to 5 mM converted Ca²⁺ dependence of InsP₃R3 from "narrow" shape to "square" shape; 5), ATP-induced change in the shape of InsP₃R3 Ca²⁺ dependence was mainly due to an >200-fold reduction in the apparent affinity of the Ca²⁺-inhibitory site; 6), the apparent Ca²⁺ affinity of the Ca²⁺ sensor region (Cas) determined in biochemical experiments is equal to 0.23 µM Ca²⁺ for RT1-Cas, 0.16 µM Ca²⁺ for RT2-Cas, and 0.10 µM Ca²⁺ for RT3-Cas; and 7), Ca²⁺ sensitivity of InsP₃R1 and InsP₃R3 isoforms recorded in the presence of 2 µM InsP₃ and 0.5 mM ATP or 2 µM InsP₃ and 5 mM ATP can be exchanged by swapping their Cas regions. Obtained results provide novel information about functional properties of mammalian InsP₃R isoforms and support the importance of the Ca²⁺ sensor region (Cas) in determining the sensitivity of InsP₃R isoforms to modulation by Ca²⁺.

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