Alternative splicing unmasks dendritic and axonal targeting signals in metabotropic glutamate receptor 1.

Precise targeting of neurotransmitter receptors to different neuronal compartments is a fundamental step for the establishment and function of synaptic circuitry. Group I metabotropic glutamate receptors, mGluR1 and mGluR5, control glutamatergic neurotransmission by acting both postsynaptically and presynaptically. Four alternatively spliced variants of the mGluR1 gene exist, which differ in their signaling properties and subcellular localization. The present study was undertaken to identify the molecular signals responsible for trafficking of these receptors to different neuronal compartments. Here we report that targeting of mGluR1 to dendrites and axons of transfected retina neurons is controlled by alternative splicing. We have identified in the tail of the receptor a tripeptide motif, which is necessary and sufficient to exclude the splice variant mGluR1b from distal dendrites and to drive it to the axon. This motif, which is present in all the mGluR1 receptors, is masked in mGluR1a by a dominant dendritic signal sequence harbored by the extended C-terminal tail of this splice variant. Furthermore, we show that the identified axonal and dendritic targeting signals are also necessary and sufficient to localize mGluR1b and mGluR1a to the apical and basolateral compartment of Madin-Darby canine kidney cells, respectively, consistent with the existence of common trafficking components for polarized targeting in epithelial cells and neurons.