Abstract
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.
Highlights
IntroductionMany regions of the nervous system exhibit spontaneous biochemical and electrical activity
During development, many regions of the nervous system exhibit spontaneous biochemical and electrical activity
We used a dual imaging technique to record both spontaneous and evoked changes in calcium levels and PKA activity in retinal ganglion cells (RGCs) somas, where it is likely that multiple pathways for calcium dependent cAMP production will coexist[21]
Summary
Many regions of the nervous system exhibit spontaneous biochemical and electrical activity. These early forms of activity, which can occur either on a cell-by-cell basis or correlated across cells by early synaptic connections, play a critical role in various developmental processes in the formation of neural circuits [for review, see1,2]. Prior to the onset of vision, retinas exhibit highly patterned, spontaneous activity, termed retinal waves [for review, see 3]. At the level of individual retinal ganglion cells (RGCs), retinal waves drive periodic bursts of depolarization, lasting roughly 2–4 seconds, occurring about once per minute [4,5]. There is growing evidence that periodic depolarizations in RGCs drive events critical for circuit development via activation of the cAMP/PKA cascade. Retinal activity is critical for mediating RGC survival, a process that is dependent on cAMP [6,7]
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