A HCO3−-dependent mechanism involving soluble adenylyl cyclase for the activation of Ca2+ currents in locus coeruleus neurons

•Hypercapnia-induced Increased HCO3− activates Ca2+ channels in LC neurons.•This pathway involves activation of sAC, increased cAMP and activation of PKA.•Intracellular HCO3− can be a chemosensitive signaling molecule in LC neurons.•Intracellular Ca2+ can play a role in central chemosensitivity in LC neurons.•Altered sAC function could contribute to breathing and/or panic disorders.

Hypercapnic acidosis activates Ca2+ channels and increases intracellular Ca2+ levels in neurons of the locus coeruleus, a known chemosensitive region involved in respiratory control. We have also shown that large conductance Ca2+-activated K+ channels, in conjunction with this pathway, limits the hypercapnic-induced increase in firing rate in locus coeruleus neurons. Here, we present evidence that the Ca2+ current is activated by a HCO3−-sensitive pathway. The increase in HCO3− associated with hypercapnia activates HCO3−-sensitive adenylyl cyclase (soluble adenylyl cyclase). This results in an increase in cyclic adenosine monophosphate levels and activation of Ca2+ channels via cyclic adenosine monophosphate-activated protein kinase A. We also show the presence of soluble adenylyl cyclase in the cytoplasm of locus coeruleus neurons, and that the cyclic adenosine monophosphate analogue db-cyclic adenosine monophosphate increases Ca2+i. Disrupting this pathway by decreasing HCO3− levels during acidification or inhibiting either soluble adenylyl cyclase or protein kinase A, but not transmembrane adenylyl cyclase, can increase the magnitude of the firing rate response to hypercapnia in locus coeruleus neurons from older neonates to the same extent as inhibition of K+ channels. This article is part of a Special Issue entitled: The role of soluble adenylyl cyclase in health and disease.