Hypoxic modulation of L-type Ca2+ channels in inspiratory brainstem neurones: Intracellular signalling pathways and metabotropic glutamate receptors

Brief hypoxia (2 min) enhances the activity of L-type Ca2+ (Ca-L) channels. The effect is dye to glutamate release and concomitant stimulation of meta botropic glutamate receptors of the mGLUR1/5 type [22] [S.L. Mironov, D.W. Richter, L-type Ca2+ channels in inspiratory neurones and their modulation by hypoxia, J. Physiol. 512 (1998) 75-87.]. Besides increasing single chann el activity, hypoxia induces a negative shift of the activation curve and s lows down the inactivation of the Ca-L current. In the present study we inv estigated these effects further, aiming to reveal intracellular signalling pathways that mediate the coupling between mGLURs and Ca-L channels. Channe l activity was recorded in cell-attached patches from inspiratory brainstem neurones of neonatal mice (PG-ll). Ca-L channels were inhibited by the mGl uR2/3 agonists. mGluR1/5 agonists accelerated and mGluR2/3 agonists suppres sed the respiratory output, and correspondingly modified the hypoxic respon se of the respiratory center. Ca-L channels were also modulated by protein kinase C-L but this did not prevent the hypoxic modification of channel act ivity. G-protein activators enhanced and G-protein inhibitors suppressed th e Ca-L channel activity, and in the presence of these agents the effects of hypoxia were abolished. Ryanodine but not thapsigargin inhibited the chann el activity and occluded the hypoxic potentiation. Only G-protein-specific agents and ryanodine prevented the slowing down of inactivation induced by hypoxia. Our data indicate that coupling between mGluR1/5 and Ca-L channels is mediated by pathways that utilize G-proteins and ryanodine receptors. G lutamate release and concomitant activation of Ca-L channels are responsibl e for accelerating of respiratory rhythm during early hypoxia. (C) 2000 Els evier Science B.V. All rights reserved.