This seeming dual competing action of AKAP79/150 is unexpected an

This seeming dual competing action of AKAP79/150 is unexpected and intriguing. Recent structural and biochemical studies have revealed the stoichiometry of the core AKAP79 complex as a dimer with two CaN heterodimers, a PKA homodimer, with PKA binding to each AKAP79 protomer (Gold

et al., 2011). Thus, there lies the tempting possibility that AKAP79/150 not only brings PKA, PKC, and CaN to both L-type Ca2+ channels and M-type K+ channels, but it also physically couples one channel to the other in the same macromolecular complex, perhaps via the two selleck kinase inhibitor protomers of the AKAP79/150 dimer (Gold et al., 2011). Both channels are widespread with overlapped expression in the nervous system, with KCNQ2/3 clustered at the axon initial segments and nodes of Ranvier (Devaux et al., 2004; Klinger et al., 2011; Pan et al., 2006; Shah et al., 2008), GSK3 inhibitor and L channels concentrated in the cell bodies and proximal dendrites

of central neurons (Hell et al., 1993). Recent findings in ventricular myocytes might shed some light on the role of AKAP79/150 in physical coupling between ion channels. CaV1.2 channels in those cells physically interact with each other at their carboxyl tails by AKAP79/150, resulting in the amplification of Ca2+ influx and excitation-contraction coupling (Dixon et al., 2012). Thus, the interaction between L channels and M channels could serve to fine-tune the activity of various neural circuits in an activity-dependent manner. Why should L channels, which underlie no more than 15% of ICa in rodent SCG neurons, be so critical for NFAT activation? Our hypothesis is that opening of specifically CaV1.3, as the dominant L channel in SCG ( Lin et al., 1996), creates an elevated local Ca2+i next signal that is sensed by CaM and CaN recruited by AKAP79/150 to the microdomain of CaV1.3 channels. Although we did not rigorously test for physical association of AKAP79/150 with CaV1.3 channels using FRET or coIP

as was done in the hippocampus for CaV1.2 ( Oliveria et al., 2007), we strongly predict that such intimate association must be the case also in sympathetic ganglia. Interestingly, blockade of the N channels that dominate ICa in sympathetic neurons also abolished NFATc1 nuclear translocation, in addition to most of the 50 K+ or ACh-induced [Ca2+]i rises. Another lab investigating NFAT translocation in the same SCG cells has suggested that influx through N, not L, channels to be the driving force for NFAT activation by electrical stimulation ( Hernández-Ochoa et al., 2007), a result that might be compatible with the dual requirement found here. If L channels play a central role in CaN/NFAT activation by clustering the CaV1.3/CaM/CaN complex through AKAP79/150, why then is there a requirement for N channels? CaN is thought to rapidly dissociate from the AKAP79 complex to interact with NFAT ( Li et al., 2012). Dephosphorylated NFAT then translocates from cytoplasm to nucleus, which requires at least 5–10 min.

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