The Role of Calcium in Central Respiratory Control Neurons

Abstract

<p>The cellular pathways that underlie central respiratory control have been implicated in several respiratory diseases including Sudden Infant Death Syndrome and sleep apnea. Central respiratory control involves neurons from several brainstem regions whose firing rate is altered in response to changes in C02. Most research has focused on the role of changes of pH and pH-sensitive ion channels as the basis for neuronal chemosensitive responses to C02. Little is known, however, about the potential role of Ca2+ in central chemosensitive signaling. We have evidence that high C02 activates L-type Ca2+ channels in the noradrenergic neurons of the locus coeruleus (LC), a known chemosensitive region involved in respiratory control. Our studies use electrophysiology to address the postnatal development of an L-type Ca2+ current in these cells that is sensitive to changes in C02. The presence of Ca2+ -activated potassium channels (KCa) in conjunction with this pathway raises the possibility that activation of KCa channels by elevated intracellular Ca2+ may serve to limit the high C02-induced increased firing rate in LC neurons. The activity of these Ca2+ channels increases dramatically over the first two weeks of life in neonatal rats, suggesting that the chemosensitive response of LC neurons may be most prominent shortly after birth. This agrees with our studies of the developmental changes of LC responsiveness to increased C02 during early life. We have also studied the mechanism by which increased C02 activates Ca2+ channels. We have evidence that L-type Ca2+ current is activated by increased intracellular HC03 which activates a HC03-sensitive adenylate cyclase (sAC). This results in subsequent phosphorylation and activation of L-type calcium channels via cAMPactivated protein kinase A. Our work indicates a novel role for Ca2+ in controlling chemosensitive signaling. Disruption of this pathway may lead to breathing instabilities associated with respiratory diseases. Supported by NIH Grant R01-HLS6683-13.</p><p>This presentation occurred at the Wright State University Campus-Wide Celebration of Research, Scholarship and Creative Activities on April 16, 2010</p>