(840) of mGluR5a by PKC interferes with the signal transduction through mGluR5a. We hypothesized that repetitive phosphorylation and dephosphorylation of mGluR5a could induce [Ca2ϩ] i oscillations by signaling on and off. In mGluR1␣, nonphosphorylation at aspartate (854) produces a non-oscillatory and PKC activator-resistant Ca 2ϩ response (9). This previous study provides the first evidence that an agonist can produce oscillatory/non-oscillatory patterns of Ca 2ϩ response by stimulating different receptor subtypes. However, it remained uncertain whether and how these two mGluRs control different cellular processes depending on their oscillatory/non-oscillatory Ca 2ϩ responses. We report here that prolonged stimulation of mGluR1␣ induced an increase in [Ca2ϩ] i that consisted of an initial transient peak and a subsequent steady plateau or an oscillatory increase in [Ca 2ϩ ] i . The transient phase was largely attributed to Ca 2ϩ release from intracellular Ca 2ϩ stores, but the sustained phase was solely due to Ca 2ϩ influx through a mGluR1␣ receptor-operated Ca 2ϩ channel. On the other hand, prolonged stimulation of mGluR5a continuously induced [Ca 2ϩ ] i oscillations through mobilization of Ca 2ϩ from the intracellular Ca 2ϩ stores. The coupling mechanism in the sustained phase of Ca 2ϩ response is determined by oscillatory/non-oscillatory patterns of the initial Ca 2ϩ response but not by the receptor identity. Thus, during prolonged stimulation of mGluRs, oscillatory/nonoscillatory patterns of Ca 2ϩ response lead to different coupling mechanisms in Ca 2ϩ signaling. MATERIALS AND METHODSFura-2 acetoxymethyl ester (Fura-2/AM) and phorbol-12-myristate-13-acetate (PMA) were from Wako Pure Chemical Industries. SK&F96365 and nimodipine were from Funakoshi. The mGluR1␣ antagonist, 1a-(N-phenyl)carbamoyl-1a,7a-dihydro-7(1H)-hydroxyiminocyclopropa[b]chromen (10) was synthesized in our laboratory.For construction of the mutant receptors, mGluR1␣(T) and mGluR5a(D), aspartate (854) of mGluR1␣ and threonine (840) of mGluR5a were changed into threonine and aspartate, respectively, as described previously (9). The cDNA encoding rat mGluR1␣, mGluR5a,

Metabotropic glutamate receptor type 1 (mGluR1) is thought to play important roles in the neurotransmission and pathogenesis of several neurological disorders. Here, we describe the radioligand binding properties and pharmacological effects of a newly synthesized, high-affinity, selective, and noncompetitive mGluR1 antagonist, 6-amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a] for mGluR1 over mGluR subtypes 2 to 7, ionotropic glutamate receptors, and other receptor, transporter, and ion channel targets. In in vivo experiments, orally administered YM-298198 showed a significant analgesic effect in streptozotocin-induced hyperalgesic mice at doses (30 mg/kg) that did not cause Rotarod performance impairment, indicating that it is also useful even for in vivo experiments. In conclusion, YM-298198 is a newly synthesized, high-affinity, selective, and noncompetitive antagonist of mGluR1 that will be a useful pharmacological tool due to its highly active properties in vitro and in vivo. Its radiolabeled form [ 3 H]YM-298198 will also be a valuable tool for future investigation of the mGluR1.

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