Metabotropic Glutamate Receptor Modulation of Glutamate Responses in the Suprachiasmatic Nucleus

Abstract

Glutamate is the primary excitatory transmitter in the suprachiasmatic nucleus (SCN). Ionotropic glutamate receptors (iGluRs) mediate transduction of light information from the retina to the SCN, an important circadian clock phase shifting pathway. Metabotropic glutamate receptors (mGluRs) may play a significant modulatory role. mGluR modulation of SCN responses to glutamate was investigated with fura-2 calcium imaging in SCN explant cultures. SCN neurons showed reproducible calcium responses to glutamate, kainate, and N-methyl-D-aspartate (NMDA). Although the type I/II mGluR agonists L-CCG-I and t-ACPD did not evoke calcium responses, they did inhibit kainate- and NMDA-evoked calcium rises. This interaction was insensitive to pertussis toxin. Protein kinase A (PKA) activation by 8-bromo-cAMP significantly reduced iGluR inhibition by mGluR agonists. The inhibitory effect of mGluRs was enhanced by activating protein kinase C (PKC) and significantly reduced in the presence of the PKC inhibitor H7. Previous reports show that L-type calcium channels can be modulated by PKC and PKA. In SCN cells, about one-half of the calcium rise evoked by kainate or NMDA was blocked by the L-type calcium channel antagonist nimodipine. Calcium rises evoked by K+ were used to test whether mGluR inhibition of iGluR calcium rises involved calcium channel modulation. These calcium rises were primarily attributable to activation of voltage-activated calcium channels. PKC activation inhibited K+-evoked calcium rises, but PKC inhibition did not affect L-CCG-I inhibition of these rises. In contrast, 8Br-cAMP had no effect alone but blocked L-CCG-I inhibition. Taken together, these results suggest that activation of mGluRs, likely type II, modulates glutamate-evoked calcium responses in SCN neurons. mGluR inhibition of iGluR calcium rises can be differentially influenced by PKC or PKA activation. Regulation of glutamate-mediated calcium influx could occur at L-type calcium channels, K+ channels, or at GluRs. It is proposed that mGluRs may be important regulators of glutamate responsivity in the circadian system.

Driving Cellular Plasticity and Survival Through the Signal Transduction Pathways of Metabotropic Glutamate Receptors

“…As a result, the modulation of intracellular calcium by the mGluR system has proven to be necessary for neuronal development, such in the cochlear nucleus magnocellular neurons (Zirpel, L et al, 2000) and in maturing hippocampal neurons (Maiese, K et al, 1999a). Furthermore, group I mGluR1 facilitates L-type voltage-dependent calcium channels currents through PKC (Endoh, T, 2004) and group II mGluRs can control calcium flux in the suprachiasmatic nucleus that may oversee circadian function (Haak, LL, 1999). In astrocytes, both group I and group II mGluRs have been associated with the generation of calcium oscillations (Zur Nieden, R and Deitmer, JW, 2005).…”

Protein Kinase C Differentially Regulates Entrainment of the Mammalian Circadian Clock

“…The absence of a significant increase in PKC isozyme mRNA expression may contribute to the lack of PKC involvement in low-level light stimuli at this circadian time; however, saturating light may act to initiate PKC expression, hence recruiting PKC as a signaling mediator. A possible mechanism may involve metabotropic glutamate receptors (mGluRs), found within the SCN, which are capable of providing the diacylglycerol and calcium required for classic and novel PKC isozyme activities, representing a viable pathway through which PKC activation may occur in response to high light intensities (Gannon & Millan, 2011;Haak, 1999). Subsaturating intensities of light show only weak activation of mGluRs within retinal bipolar cells; however, saturating light results in sufficient glutamate release to stimulate mGluRs and subsequent PKC activity (Awatramani & Slaughter, 2001;Cartmell & Schoepp, 2000).…”

Modulation of photic response by the metabotropic glutamate receptor agonist t-ACPD

“…mGluR activation in the SON has been shown to enhance glutamate release in the SON [25], an effect that, if present in the SCN, would support an increase in light-induced phase shifts. Inhibition of GABAergic transmission would also help to explain an apparent conflict between these results and the finding that ACPD inhibits NMDA-induced calcium influx in SCN explant cultures [26]. Inhibition of calcium influx would be expected to inhibit the phase shifting effects of light, since activation of NMDA receptors is a critical step in light-induced phase shifts [12;13].…”