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Functional Characterization of Mammalian Inositol 1,4,5-Trisphosphate Receptor Isoforms

Huiping Tu ^*, Zhengnan Wang ^*, Elena Nosyreva ^*, Humbert De Smedt  and Ilya Bezprozvanny ^*

^* Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390 USA; and Laboratorium voor Fysiologie, K.U.Leuven, B-3000, Leuven, Belgium

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.

Inositol 1,4,5-trisphosphate receptors (InsP₃R) play a key role in intracellular calcium (Ca²⁺) signaling. Three mammalian InsP₃R isoforms—InsP₃R type 1 (InsP₃R1), InsP₃R type 2 (InsP₃R2), and InsP₃R type 3 (InsP₃R3) are expressed in mammals, but the functional differences between the three mammalian InsP₃R isoforms are poorly understood. Here we compared single-channel behavior of the recombinant rat InsP₃R1, InsP₃R2, and InsP₃R3 expressed in Sf9 cells, reconstituted into planar lipid bilayers and recorded with 50 mM Ba²⁺ as a current carrier. We found that: 1), for all three mammalian InsP₃R isoforms the size of the unitary current is 1.9 pA and single-channel conductance is 74–80 pS; 2), in optimal recording conditions the maximal single-channel open probability for all three mammalian InsP₃R isoforms is in the range 30–40%; 3), in optimal recording conditions the mean open dwell time for all three mammalian InsP₃R isoforms is 7–8 ms, the mean closed dwell time is 10 ms; 4), InsP₃R2 has the highest apparent affinity for InsP₃ (0.10 µM), followed by InsP₃R1 (0.27 µM), and then by InsP₃R3 (0.40 µM); 5), InsP₃R1 has a high-affinity (0.13 mM) ATP modulatory site, InsP₃R2 gating is ATP independent, and InsP₃R3 has a low-affinity (2 mM) ATP modulatory site; 6), ATP modulates InsP₃R1 gating in a noncooperative manner (n_Hill = 1.3); 7), ATP modulates InsP₃R3 gating in a highly cooperative manner (n_Hill = 4.1). Obtained results provide novel information about functional properties of mammalian InsP₃R isoforms.

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