Sorting nexin 27 regulates basal and stimulated brush border trafficking of NHE3

Abstract

In polarized epithelial cells, SNX27 regulates PDZ domain–directed trafficking of NHE3 from endosomes to the plasma membrane and increases the stability of brush border NHE3. This establishes SNX27 as an important regulator of polarized sorting in epithelial cells.

SNX27, a protein involved in down syndrome, regulates GPR17 trafficking and oligodendrocyte differentiation

“…Our findings show that: (i) mutations of the GPR17 PDZ-binding motif impair receptor trafficking and recycling to the plasma membrane; (ii) SNX27, a member of the retromer complex involved in protein trafficking from early endosomes back to the plasma membrane McGough et al, 2014;Steinberg et al, 2013;Temkin et al, 2011), interacts with the C-terminal domain of GPR17 and is required for its recycling; (iii) silencing of SNX27 significantly increases GPR17 degradation, and this correlates with increased expression of the myelin proteins MAG and MBP and with accelerated OL differentiation in vitro. Whereas a great number of studies has reported a role of SNX27 in controlling glutamate receptor and ion channel expression with important implications in synaptic transmission (Balana et al, 2011;Damseh et al, 2015;Hussain et al, 2014;Loo et al, 2014;Munoz and Slesinger, 2014;Wang et al, 2013Wang et al, , 2014, very few data are available on the physiological and pathological functions of SNX27 in other cell types (Singh et al, 2015). On the other hand our findings reveal that myelination is decreased in Ts65Dn mice, in line with previous data showing hypomyelination in human DS brains (Abraham et al, 2012; see also below).…”

Phosphorylation of NHE3-S719regulates NHE3 activity through the formation of multiple signaling complexes

“…For instance, binding of the NHE3 C-terminus to CHP and SNX27 was shown to be necessary for normal basal NHE3 activity, and binding to SNX27 is also necessary for the stimulated exocytosis involved in acute increases in NHE3 activity (Pang et al ., 2001; Zaun et al ., 2008; Singh et al ., 2015). One of the implications of the present study is that changes in NHE3 lipid raft association via changes in its C-terminus may be a more general mechanism for NHE3 regulation than previously suspected and could explain previous studies that concentrated on effects of single binding partners of NHE3.…”

Role of the sodium‐hydrogen exchanger in mediating the renal effects of drugs commonly used in the treatment of type 2 diabetes

“…The trafficking of renal tubular NHE3 involves specific phosphorylation sites, which may be selectively targeted by novel compounds . Alternatively, innovative therapeutic agents might focus on interfering with the binding proteins or kinases that are required for the phosphorylation, trafficking or membrane localization of NHE3 in renal tubular cells . The development of such novel agents might allow physicians to directly address one of the primary mechanisms responsible for the glomerular hyperfiltration that leads to diabetic nephropathy…”

“…13 Alternatively, innovative therapeutic agents might focus on interfering with the binding proteins or kinases that are required for the phosphorylation, trafficking or membrane localization of NHE3 in renal tubular cells. 26,[243][244][245][246] The development of such novel agents might allow physicians to directly address one of the primary mechanisms responsible for the glomerular hyperfiltration that leads to diabetic nephropathy. 98 relationships has a bearing on the topic of this paper.…”