Glutamate is the primary excitatory transmitter in the suprachiasmatic nucl
eus (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 glutama
te was investigated with fura-2 calcium imaging in SCN exp]ant cultures. SC
N 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 N
MDA-evoked calcium rises. This interaction was insensitive to pertussis tox
in Protein kinase A (PKA) activation by 8-bromo-cAMP significantly reduced
iGluR inhibition by mGluR agonists. The inhibitory effect of mGluRs was enh
anced by activating protein kinase C (PKC) and significantly reduced in the
presence of the PKC inhibitor H7. Previous reports show that L-type calciu
m 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 calci
um channel antagonist nimodipine. Calcium rises evoked by K+ were used to t
est whether mGluR inhibition of iGluR calcium rises involved calcium channe
l 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 nest affect L-CCG-I inhibition of the
se rises. In contrast, 8Br-cAMP had no effect alone but blocked L-CCG-I inh
ibition. Taken together, these results suggest that activation of mGluRs, l
ikely type II, modulates glutamate-evoked calcium responses in SCN neurons.
mGluR inhibition of iGluR calcium rises can be differentially influenced b
y PKC or PKA activation. Regulation of glutamate-mediated calcium influx co
uld occur at L-type calcium channels, K+ channels, or at GluRs. it is propo
sed that mGluRs may he important regulators of glutamate: responsivity in t
he circadian system.