Fig. 8
From: Modifying Rap1-signalling by targeting Pde6δ is neuroprotective in models of Alzheimer’s disease
Model illustrating how Pde6δ links different pools of Rap1 to Ca2+ homeostasis, neuronal excitability, cognition and neuronal survival. The Rap1-ERK1/2 cascade emanating from endomembranes represses VGCC and AMPA-R but increases GABAB receptor activity, thus favouring a reduction in neuronal activity. On the other hand, a plasma membrane associated pool of basal Rap1-ERK1/2 activity inhibits Kv4.2 channels, which promotes neuronal activity. Assuming that like for Ras [41], removal of Rap1 from the plasma membrane is endocytosis dependent, neuronal activity coinciding with endocytosis will redistribute Rap1 towards endomembranes. This Rap1 redistribution is geared towards lowering neuronal excitability, it could represent a natural feedback control to keep neuronal activity and VGCC mediated Ca2+ influx within certain limits and protecting neurons. Rap1 recycling from endomembranes to the plasma membrane is facilitated by Pde6δ. Thus, inhibition of Rap1 plasma membrane recycling by REM augments the small GTPase’s presence and activity at endomembranes, while depleting it from the plasma membrane. As a result, under conditions of persistent excessive neuronal activity (such as in AD and epilepsy), REM rearranges the different pools of Rap1 towards restraining Ca2+ influx and neuronal excitability, resulting in neuroprotection. (In blue: Rap1-ERK1/2 actions at different membranes; orange arrows indicate Rap1-ERK1/2 functions altered by REM)