Hypoxic modulation of L-type Ca(2+) channels in inspiratory brainstem neurones: intracellular signalling pathways and metabotropic glutamate receptors.
Brief hypoxia (2 min) enhances the activity of L-type Ca(2+) (Ca(L)) channels. The effect is due to glutamate release and concomitant stimulation of metabotropic glutamate receptors of the mGLUR1/5 type [22] [S.L. Mironov, D.W. Richter, L-type Ca(2+) channels in inspiratory neurones and their modulation by hypoxia, J. Physiol. 512 (1998) 75-87.]. Besides increasing single channel activity, hypoxia induces a negative shift of the activation curve and slows down the inactivation of the Ca(L) current. In the present study we investigated these effects further, aiming to reveal intracellular signalling pathways that mediate the coupling between mGLURs and Ca(L) channels. Channel activity was recorded in cell-attached patches from inspiratory brainstem neurones of neonatal mice (P6-11). Ca(L) channels were inhibited by the mGluR2/3 agonists. mGluR1/5 agonists accelerated and mGluR2/3 agonists suppressed the respiratory output, and correspondingly modified the hypoxic response of the respiratory center. Ca(L) channels were also modulated by protein kinase C, but this did not prevent the hypoxic modification of channel activity. G-protein activators enhanced and G-protein inhibitors suppressed the Ca(L) channel activity, and in the presence of these agents the effects of hypoxia were abolished. Ryanodine but not thapsigargin inhibited the channel 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. Glutamate release and concomitant activation of Ca(L) channels are responsible for accelerating of respiratory rhythm during early hypoxia.
Mironov
S L
SL
II Department of Physiology, University of Göttingen, Humboldtallee 23, D-37073, Göttingen, Germany. sergej@neuro-physiol.med.uni-goettingen.de
Richter
D W
DW
D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008526:Medulla Oblongata / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011042:Poisons / Q000009:adverse effects; D011493:Protein Kinase C / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000378:metabolism*; D012125:Respiratory Center / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D012143:Respiratory Physiological Phenomena / Q000187:drug effects; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D020746:Calcium Channels, L-Type; D011042:Poisons; D018094:Receptors, Metabotropic Glutamate; D019837:Ryanodine Receptor Calcium Release Channel; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D002118:Calcium