Functional coupling between ryanodine receptors and L-type calcium channels in neurons

Abstract

In skeletal muscle, L-type Ca2+ channels act as voltage sensors to control ryanodine-sensitive Ca2+ channels in the sarcoplasmic reticulum. It has recently been demonstrated that these ryanodine receptors generate a retrograde signal that modifies L-type Ca2+ -channel activity. Here we demonstrate a tight functional coupling between ryanodine receptors and L-type Ca2+ channel in neurons. In cerebellar granule cells, activation of the type-1 metabotropic glutamate receptor (mGluR1) induced a large, oscillating increase of the L-type Ba2+ current. Activation occurred independently of inositol 1,4,5-trisphosphate and classical protein kinases, but was mimicked by caffeine and blocked by ryanodine. The kinetics of this blockade were dependent on the frequency of Ba2+ current stimulation. Both mGluR1 and caffeine-induced increase in L-type Ca2+ -channel activity persisted in inside-out membrane patches. In these excised patches, ryanodine suppressed both the mGluR1- and caffeine-activated L-type Ca2+ channels. These results demonstrate a novel mechanism for Ca2+ -channel modulation in neurons.

cADP-ribose potentiates cytosolic Ca2+ elevation and Ca2+ entry via L-type voltage-activated Ca2+ channels in NG108-15 neuronal cells

“…Our results support and extend this novel idea that L-type VACCs and RyRs are functionally coupled, and we provide the first evidence for the involvement of cADPR in this coupling, as shown in Scheme 1. This coupling may not be the direct interaction, because ryanodine had no inhibitory effect on the control VACC activity [12].…”

“…Such a signal is termed retrograde signalling [10]. Chavis et al have shown a similar signal in cerebellar granule cells [12], where RyRs activated by type-1 metabotropic glutamate receptors increase VACC activity. Since it has been reported that cerebellar granule cells possess RyR-2 and RyR-3 [5,6], the retrograde signal from RyR-2 or RyR-3 may target the L-type VACCs.…”

“…For the retrograde signal in neurons, Chavis et al [12] postulated that some intermediate factor physically links RyRs with the L-type VACCs (Scheme 1C). An alternative idea is that Ca# + exhaustion in ryanodine-sensitive Ca# + stores elicited by cADPR and CICR may trigger VACC activation, which in turn refills the stores by Ca# + influx by a positive-feedback mechanism (Scheme 1D).…”

“…Whereas RyR-1 is coupled to L-type voltage-activated Ca# + channels (VACCs) through proteinprotein interactions [10], such direct coupling has not been shown in RyR-2 and RyR-3. In neurons, instead, a link from Ntype VACCs to RyRs (an orthograde influence) [11] and a functional coupling from RyRs to L-type VACCs (a retrograde signal) [12] have been reported. The molecular mechanism and responsible second messengers for such interactions are not clear.…”

The Metabotropic Glutamate Receptor mGluR5 Induces Calcium Oscillations in Cultured Astrocytes via Protein Kinase C Phosphorylation

“…Chavis et al (1996) recently reported that activation of mUluRl induces oscillatory Ba 2~currents in cerebellar granule cells by stimulating a coupling between ryanodine receptors and L-type Ca2~channels. This stimulation of oscillatory currents occurred independently of 1P 3 formation and was blocked by ryanodine (Chavis et al, 1996). Addition of ryanodine to cultured astrocytes, however, had no effect on [Ca 2~]õ scillations induced by lS,3R-ACPD (Fig.…”