IP 3 Receptors as Huntington's Target

Abstract

A search for binding partners for the type 1 receptor for inositol 1,4,5-trisphosphate (IP 3 R1), which releases Ca 2+ from intracellular stores in response to the intracellular messenger IP 3 , has turned up a target that may help explain the devastating loss of function in medium spiny striatal neurons associated with the neurodegenerative disease known as Huntington's disease. Huntington's disease is caused by a polyglutamine expansion in the huntingtin protein (Htt). The mutant, expanded form of Htt associates more readily than does the wild-type protein with another protein called Htt-associated protein-1 (HAP1). Tang et al. found HAP1 in a yeast two-hybrid screen for proteins that bound with the C-terminal portion of rat IP 3 R1. In vitro and in vivo, IP 3 R1 appeared to associate with either Htt or HAP1 or to be part of a ternary complex of the proteins. Functional assays of IP 3 R1 reconstituted in planar lipid bilayers showed that the IP 3 R1 channel was sensitized to IP 3 in the presence of mutant expanded Htt, but not wild-type Htt. When medium spiny striatal neurons in primary culture were transfected with expanded Htt, Ca 2+ release from intracellular stores became more sensitive to small amounts of an agonist for metabotropic glutamate receptors. Other potential targets of Htt have been proposed before, including certain N -methyl-D-aspartate receptors (NMDARs), which, when activated, allow entry of extracellular Ca 2+ into the cell. The authors propose that combined effects of mutant Htt on NMDARs and IP 3 R1 could contribute to abnormally strong Ca 2+ signaling, which might lead to neuronal malfunction or apoptosis. T.-S. Tang, H. Tu, E. Y. W. Chan, A. Maximov, Z. Wang, C. L. Wellington, M. R. Hayden, I. Bezprozvanny, Huntingtin and huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1. Neuron 39 , 227-239 (2003). [Online Journal]