The Obestatin/G Protein-Coupled Receptor 39 (GPR39) System in Human Stomach: Its Role on Pepsinogen I Secretion (original) (raw)

Background and aim: The large conductance Ca2+-activated K+ (BK) channel regulates smooth muscle contractility by modulating membrane potential, and age-associated changes in BK channel expression may contribute to the development of motility disorders of the gastrointestinal tract. Advanced glycation end products (AGEs) result from a slow chemical reaction between the sugars and amine groups in proteins, lipids, or DNA in the body. AGEs have been observed to accumulate in various organs with aging. In this study, we examined whether AGEs accumulation with aging would be related to BK-β1 subunits upregulation and contractile dysfunction of colonic SMCs. Methods: Male Sprague-Dawley (SD) rats were randomly divided into four experimental groups: juvenile, young, middleaged, and aged. Colonic transit time and colonic SM strip contractility in the groups were measured. Levels of AGEs and AGEs receptor (RAGE) in serum and colon muscle layer were tested. Primary cultured colonic smooth muscle cells (SMCs) were used in complementary in vitro studies. In the presence and absence of AGEs-BSA, SMC were treated with the ERK1/2 inhibitors PD98059 and U0126, the P38-MAPK inhibitors SB203580 and SB202190, or the PI3K inhibitors LY294002 or RAGE small interfering RNA (siRNA). BK-β1 subunits expression, BK channel currents, [Ca2+]i and myosin light chain (MLC) in SMC were also tested. Results: Colonic motility decreases in an age-dependent manner, while the serum AGEs and colonic SM RAGE and BK-β1 subunits expression increase in an age-dependent manner. In primary colonic SMCs, AGEs-BSA increased BK-β1 subunits expression in a time-and dose-dependent manner without changing the sigle BK channel currents. In addition, AGEs-BSA decrease intracellular Ca2+ concentrations and myosin light chain phosphorylation in a dose-dependent manner. The P38-MAPK inhibitors SB203580 and SB202190 could significantly inhibited AGEs-BSA induced BK-β1 subunits upregulation. After interfer RAGE expression with RAGE siRNA, AGEs-BSA induced BK-β1 subunits upregulation could also be partially reversed. Conclusions: This study suggested that AGEs/ RAGE participate in aging-associated colonic dysmotility by upregulation of BK channel β1subunit in colonic SMC. This effect depends on the activation of P38-MAPK pathway.

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