Editors' ChoiceNeuroscience

IP3 Receptors as Huntington's Target

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Science's STKE  29 Jul 2003:
Vol. 2003, Issue 193, pp. tw290-TW290
DOI: 10.1126/stke.2003.193.tw290

A search for binding partners for the type 1 receptor for inositol 1,4,5-trisphosphate (IP3R1), which releases Ca2+ from intracellular stores in response to the intracellular messenger IP3, 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 IP3R1. In vitro and in vivo, IP3R1 appeared to associate with either Htt or HAP1 or to be part of a ternary complex of the proteins. Functional assays of IP3R1 reconstituted in planar lipid bilayers showed that the IP3R1 channel was sensitized to IP3 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, Ca2+ 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 Ca2+ into the cell. The authors propose that combined effects of mutant Htt on NMDARs and IP3R1 could contribute to abnormally strong Ca2+ 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]

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