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 reticulum¹. It has recently been demonstrated that these ryanodine receptors generate a retrograde signal that modifies L-type Ca²⁺-channel activity². 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 (mGluRl) 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 mGluRl-and caffeine-induced increase in L-type Ca²⁺-channel activity persisted in inside-out membrane patches. In these excised patches, ryanodine suppressed both the mGluRl- and caffeine-activated L-type Ca²⁺ channels. These results demonstrate a novel mechanism for Ca²⁺-channel modulation in neurons.