Fig. 8. Working model for the regulatory role of 14-3-3 and CaM on Kir/Gem localization and function. Since CaM and 14-3-3 compete for Kir/Gem binding, two pathways can be considered. Activation of CaM by intracellular Ca²⁺ results in association of CaM with Kir/Gem and retains it in the cytoplasm. Dissociation of CaM allows Kir/Gem to bind the Ca²⁺ channel ß-subunit, interfering with plasma membrane expression of the 1-subunit. Alternatively, in the absence of CaM activation, 14-3-3 can relocalize phosphorylated Kir/Gem from a submembranous location to the cytoplasm to block the formation of dendrite-like extensions. 14-3-3 can also relocalize Kir/Gem from the nucleus to the cytoplasm. 14-3-3 bound to Kir/Gem may be exchanged for the ß-subunit. Upon activation of CaM by Ca²⁺, Kir/Gem dissociates from the ß-subunit. Kir/Gem is in its active, GTP-bound form when located in the nucleus or bound to the ß-subunit; however, the activation state when associated with CaM or 14-3-3 remains to be determined.