Regulation of CFTR chloride channel trafficking by nedd4-2: Role of SGK1

Introduction: the cystic fibrosis transmembrane conductance regulator (cftr) chloride (cl−) channel is an essential component of epithelial cl− transport systems in many organs. cftr is mainly expressed in the lung and other tissues,such as testis,duodenum,trachea and kidney. the ubiquitin ligase neural precursor cells expressed developmentally down-regulated protein 4-2 (nedd4-2) has previously been shown to regulate abundance of several channel and carrier proteins in the plasma membrane,an effect reversed by glucocorticoid dependent kinase 1 (sgk1). methods: the present study was thus performed to elucidate the sensitivity of cftr to regulation by nedd4-2 and the serum and sgk1. to this end,the cftr was heterologously expressed in oocytes alone or together with nedd4-2 or the sgk1. the crnas encoding cftr,nedd4-2 and/or the constitutively active s422dsgk1 have been injected into xenopus oocytes. the activity of cftr was measured by the two-electrode voltage-clamp technique and cftr-mediated currents were elicited by the application of forskolin and ibmx (f/i). results: as a result,forskolin/ibmx treatment triggered camp-stimulated ion currents (icamp) in xenopus oocytes expressing cftr crna,but not in oocytes injected with water (control). co-expression of nedd4-2 markedly down-regulates the camp-stimulated ion current (icamp),an effect reversed by co-expression of the constitutively active s422dsgk1. in xenopus oocytes co-expressing cftr with s422dsgk1 the camp-stimulated ion current (icamp) was similar to that in xenopus oocytes expressing cftr alone. conclusion: the present observations suggest that cftr is a target for the ubiquitin ligase nedd4-2,which is inactivated by the sgk1. © 2017,iranian society of physiology and pharmacology. all rights reserved.