Calcium-dependent increases in protein kinase-A activity in mouse retinal ganglion cells are mediated by multiple adenylate cyclases.
Neurons undergo long term, activity dependent changes that are mediated by activation of second messenger cascades. In particular, calcium-dependent activation of the cyclic-AMP/Protein kinase A signaling cascade has been implicated in several developmental processes including cell survival, axonal outgrowth, and axonal refinement. The biochemical link between calcium influx and the activation of the cAMP/PKA pathway is primarily mediated through adenylate cyclases. Here, dual imaging of intracellular calcium concentration and PKA activity was used to assay the role of different classes of calcium-dependent adenylate cyclases (ACs) in the activation of the cAMP/PKA pathway in retinal ganglion cells (RGCs). Surprisingly, depolarization-induced calcium-dependent PKA transients persist in barrelless mice lacking AC1, the predominant calcium-dependent adenylate cyclase in RGCs, as well as in double knockout mice lacking both AC1 and AC8. Furthermore, in a subset of RGCs, depolarization-induced PKA transients persist during the inhibition of all transmembrane adenylate cyclases. These results are consistent with the existence of a soluble adenylate cyclase that plays a role in calcium-dependent activation of the cAMP/PKA cascade in neurons.
Dunn
Timothy A
TA
Neurobiology Section, Division of Biological Sciences, University of California San Diego, La Jolla, California, USA.
Storm
Daniel R
DR
Feller
Marla B
MB
D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D012160:Retina / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000378:metabolism*
D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D010727:Phosphoric Diester Hydrolases; D000262:Adenylyl Cyclases; D002118:Calcium