The simultaneous mutations of four arginine-framed tripeptides (AFTs) (R29K, R516K, R555K and R766K; 4RK) in cystic fibrosis transmembrane conductance regulator (CFTR) rescues the processing and function of the most common cystic fibrosis mutation, F508del [1]. G550E, another F508del revertant, exerts, by itself, a similar effect [2]. Recently, we demonstrated that 4RK affects mainly processing efficiency, whereas G550E appears to act directly on CFTR structure, as it rescues efficaciously F508del gating [3]. Of note, the G550E revertant is located next to G551, the site of a CF mutant (G551D) that profoundly disrupts CFTR gating. Here, we explore the effects of G550E and 4RK on the processing and gating of G551D. We used BHK cells expressing G551D-, G551D-G550E- and G551D-4RK-CFTRs, metabolic pulse-chase labelling to study protein processing and excised inside-out membrane patches to examine channel gating [3]. Data are means ± SEM of n observations; statistical analyses were performed using Student’s paired t test. Unlike F508del, G551D is processed normally. However, the processing efficiency of G551D was modulated by revertant mutants with G550E, but not 4RK, increasing processing efficiency. These data contrast with the effects of the revertants on wild-type (wt) and V562I, where 4RK, but not G550E, enhanced processing efficiency [3]. In contrast to wt, the interburst interval (IBI) of G551D was prolonged greatly and the mean burst duration (MBD) reduced with the result that P_o was diminished markedly (wt, P_o = 0.47±0.03, n = 7; G551D, P_o = 0.007±0.001, n = 8). Although both G550E and 4RK increased the P_o of G551D, they were ineffective at rescuing channel activity. Surprisingly, while both revertants attenuated markedly IBI, they also shortened MBD (G551D-G550E, P_o = 0.010±0.001, MBD = 27±4 ms, IBI = 2,772±301 ms, n = 13 for all; G551D-4RK, P_o = 0.027±0.005, MBD = 11±1 ms, IBI = 535±113 ms, n = 14 for all; p < 0.05). As a result, the gating behaviour of G551D-G550E and G551D-4RK appeared very flickery. To summarise, the revertant G550E increased the processing of G551D, but not that of wt and V562I [3], whereas, both G550E and 4RK restored function to F508del [3], but not G551D. Our data suggest that when in cis with G551D, AFTs might influence directly channel gating, arguing that 4RK, in addition to its effects on trafficking, might alter G551D folding. Thus, the effects of G550E and 4RK on protein processing and channel gating are mutation-specific.