Calcium-Dependent Increases in Protein Kinase-A Activity in Mouse Retinal Ganglion Cells Are Mediated by Multiple Adenylate Cyclases

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.

Nicotine-induced activation of soluble adenylyl cyclase participates in ion transport regulation in mouse tracheal epithelium

“…One possibility for the interaction between Ca 2+ -dependent and cAMP-dependent pathways is represented by Ca 2+ -dependent adenylyl cyclases. Therefore, we performed experiments with the adenylyl cyclase inhibitor 2'5'-dideoxyadenosine (DDA), which has been described as a cell permeable inhibitor that preferentially blocks tmAC (Landa et al, 2005;Dunn et al, 2009), and KH7, a specific inhibitor of sAC (Schmid et al, 2007). Application of DDA (50 μM, apical and basolateral) had no effect on the baseline current (p =1, n =8, Fig.…”

“…These enzymes can be grouped in transmembrane adenylyl cyclases (tmAC) and soluble adenylyl cyclases (sAC) according to their location in the cells. Both adenylyl cyclases, tmAC (tmAC1 and tmAC8) and sAC, can be activated by Ca 2+ (Dunn et al, 2009;Ferguson and Storm, 2004), providing a possible connection between Ca 2+ -and cAMPdependent signaling processes. Therefore, we here investigate the involvement of adenylyl cyclases in the nicotine-induced transepithelial ion transport.…”

A Model for Sealing Plasmalemmal Damage in Neurons and Other Eukaryotic Cells

“…Intracellular DAG concentration is increased by damage-induced Ca 2ϩ influx that activates calpain to cleave and activate phospholipase C. [Calpains are Ca 2ϩ -dependent proteases necessary for plasmalemmal sealing in many preparations Mellgren et al, 2007).] (Dunn et al, 2009). Ca 2ϩ influx also activates calpain , whose protease action rearranges the cytoskeleton, partially constricting the cut ends of a transected axon or neurite, and also increases DAG availability by activating phospholipases.…”

Interplay among cGMP, cAMP, and Ca2+ in Living Olfactory Sensory Neurons In Vitro and In Vivo

“…To measure FRET ratios, bleed through of CFP and fura-2 was corrected. To analyze fura-2 fluorescence intensity, fura-2 emission from both channels was summed, and bleed through from CFP was corrected (Dunn et al, 2009).…”