The metabotropic glutamate receptor 4 is internalized and desensitized upon protein kinase C activation

1 The metabotropic glutamate receptor 4 (mGluR4) is a Gαi‐coupled receptor that modulates glutamatergic neurotransmission. As mGluR4 expression and activation have been implicated in a number of pathological conditions and because the internalization and desensitization properties of this receptor are poorly understood, studies were designed to investigate these aspects of mGluR4 biology. 2 Neither agonist activation by L‐(+)‐2‐amino‐4‐phosphonobutyric acid (L‐AP4) nor L‐glutamate caused mGluR4 internalization when cmyc‐tagged mGluR4 was expressed in a human embryonic kidney 293 cell line as assessed by cell surface enzyme‐linked immunosorbent and immunostaining assays. Instead, a modest increase in mGluR4 surface expression was observed and found to be receptor specific as the competitive antagonist α‐cyclopropyl‐4‐phosphonophenylglycine (CPPG) blocked this effect. 3 In contrast, mGluR4 internalized when the protein kinase C (PKC) pathway was activated either by phorbol‐12‐myristate‐13‐acetate (PMA) or by the activation of the Gαq‐coupled, neurokinin 3 receptor (NK3R) when co‐expressed. This process was PKC‐dependent as the specific PKC inhibitor GF 109203X inhibited PMA and NK3R‐mediated internalization. 4 PKC activation by PMA caused desensitization of mGluR4 as measured by forskolin‐stimulated cAMP inhibition, whereas agonist activation had no effect on desensitization. 5 When mGluR4's coupling was redirected from adenylyl cyclase to phospholipase C by coexpression of a chimeric Gαqo5 protein, mGluR4 both internalized and desensitized in response to its agonists. 6 These findings demonstrate that mGluR4 internalization and desensitization are agonist‐independent unless pathways leading to the activation of PKC are induced. British Journal of Pharmacology (2006) 148, 279–290. doi:10.1038/sj.bjp.0706733