Surface expression of the K(2P)3.1 two-pore domain potassium channel is regulated by phosphorylation-dependent binding of 14-3-3, leading to suppression of coatomer coat protein I (COPI)-mediated retention in endoplasmic reticulum (ER). Here, we investigate the nature of the macromolecular regulatory complexes that mediate forward and retrograde transport. We demonstrate that (i) the channel employs two separate but interacting COPI binding sites on the N- and C-termini; (ii) disrupting COPI binding to either site interferes with the ER retention; (iii) p11 and 14-3-3 do not interact on their own; (iv) p11 binding to the C-terminal retention motif is dependent on 14-3-3; and (v) p11 is coexpressed in only a subset of tissues with K(2P)3.1, while 14-3-3 expression is ubiquitous. We conclude that K(2P)3.1 forward transport requires 14-3-3 suppression of COPI binding, whereas p11 serves a modulatory role.