A role for Seven in Absentia Homolog (Siah1a) in metabotropic glutamate receptor signaling

Paul J Kammermeier,Stephen R Ikeda

doi:10.1186/1471-2202-2-15

Paul J Kammermeier, Stephen R Ikeda

Open Access

https://doi.org/10.1186/1471-2202-2-15

Copy DOI

Journal: BMC neuroscience	Publication Date: Jan 1, 2001
Citations: 45	License type: cc-by

Affiliation: Guthrie Foundation

Abstract

BackgroundThe mammalian homologue of Seven in Absentia (Siah) can act in the ubiquitin/proteasome pathway. Recent work has shown that Siah can bind group I metabotropic glutamate receptors (mGluRs), but the functional consequences of this interaction are unknown.ResultsThe effects of coexpression of Siah on group I mGluR signaling were examined using heterologous expression in rat sympathetic, superior cervical ganglion neurons. Siah1a attenuated heterologously expressed group I mGluR-mediated calcium current inhibition, but was without effect on group II mGluR- or NE-mediated calcium current modulation via heterologously expressed mGluR2 or native a2 adrenergic receptors, respectively, indicating that the effect of Siah was specific for group I mGluRs. Surface expression and subcellular distribution of group I mGluRs were not detectably altered in the presence of Siah1a as assessed by immunoflourescence experiments with epitope tagged receptors and imaging of a GFP/mGluR fusion construct. In addition, an N-terminal Siah deletion construct, which cannot function in the proteolysis pathway, displayed effects similar to the wild type Siah1a. Finally, coexpression of calmodulin, which competes with Siah1a for binding to the C-terminal tail of group I mGluRs, reversed the effect of Siah1a on mGluR-mediated signaling.ConclusionsThese data supported the conclusion that the attenuation of mGluR signaling induced by Siah1a expression was likely a direct consequence of Siah/mGluR association rather than a result of targeting of the receptors to the proteosome. In addition, the data suggest that the binding of CaM and Siah may play an important role in the regulation of group I mGluR function.

Highlights

The mammalian homologue of Seven in Absentia (Siah) can act in the ubiquitin/ proteasome pathway
Coexpression of Siah1a with group I metabotropic glutamate receptors (mGluRs) To examine the role of Siah1a expression on mGluR function, superior cervical ganglion (SCG) neurons were injected with cDNA encoding several group I mGluRs with or without Siah1a expression
The findings described here demonstrate that the mammalian homologue of seven in absentia, Siah1a regulates the function of group I metabotropic glutamate receptors

Summary

Introduction

The mammalian homologue of Seven in Absentia (Siah) can act in the ubiquitin/ proteasome pathway. Metabotropic glutamate receptors (mGluRs) are a family of class 3 G protein-coupled receptors with important functions in the regulation of synaptic transmission, plasticity, neuronal excitability, and the regulation sensory transduction [1,2,3,4,5]. The association of mGluRs with scaffolding proteins such as Homer (group I; [20]) and PICK-1 (group III; [21]) is important in regulating mGluR localization and function [21,22,23,24]. CaM binding to both group I and group III mGluRs can be inhibited by serine/ threonine phosphorylation at specific sites [25,28] It is of interest in terms of mGluR function and localization to understand the roles of proteins which interact with these receptors

Methods

Results

Conclusion