Received for publication July 19, 2007.
Revised December 3, 2007.
Accepted for publication December 4, 2007.

CPPHA acts through a novel site as a positive allosteric modulator of group 1 metabotropic glutamate receptors

Abstract

Recent studies suggest that a novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor, mGluR5, termed VU-29, potentiates mGluR5 responses by actions at a site that is overlapping with the binding site of MPEP, a previously identified negative allosteric modulator (NAM) of this receptor. Interestingly, a structurally distinct PAM, CPPHA, does not to bind to the MPEP site. We now report that CPPHA potentiates mGluR5 responses by a mechanism that is distinct from that of VU-29. VU-29- and CPPHA-induced potentiation of mGluR5 responses are blocked by a neutral ligand at the MPEP allosteric site termed 5MPEP. However, increasing concentrations of 5MPEP induce parallel rightward shifts in the VU-29 concentration response curve (CRC) whereas 5MPEP inhibits CPPHA potentiation in a non competitive manner. Consistent with this, a mutation (A809V/mGluR5) that reduces binding of ligands to the MPEP site eliminates the effect of VU-29 but has no effect on the response to CPPHA. Conversely, a mutation that eliminates the effect of CPPHA does not alter the response to VU-29. CPPHA is also a PAM at mGluR1. Interestingly, the corresponding mutation of F585I/mGluR5 in mGluR1 (F599I/mGluR1) eliminates CPPHA's effect without altering the potentiation of a known PAM of mGluR1 (Ro 67-7476). Likewise, another mutation (V757L/mGluR1) abolishes potentiation of Ro 67-7476 has no effect on CPPHA. Finally, CPPHA does not displace binding of a radioligand for the previously characterized mGluR1 allosteric antagonist. Together, these data suggest that CPPHA acts at a novel allosteric site on both mGluR1 and 5 to potentiate responses to activation of these receptors.

Key words: Metabotropic glutamate, Gq/11 family, Func. analysis receptor/ion channel mutants, Mutagenesis/Chimeric approaches, Receptor binding studies

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