Abstract P146: Dopaminergic Stimulation Increases Gastrin Secretion via a PKA-PPAR-Alpha Pathway

Abstract

Dietary sodium stimulates renal excretion of sodium long before the sodium is enterally absorbed. Moreover, intravenously administered sodium does not stimulate as large an excretory response as sodium taken by mouth. We previously showed that sodium stimulates an increase in gastrin mRNA and protein in stomach G-cells via PPAR-α and dopamine D1 receptor (D 1 R). Studies have shown that PKA pathway is important in the regulation of PPAR-α activity, and PKA is also involved in the D 1 R pathway. Thus, we hypothesized that D 1 R may regulate PPAR-α through PKA in human G-cells in response to sodium. Human G-cells were treated with 8-Br-cAMP, a cell-permeable second messenger analog, and Rp-cAMP (RPCA), a PKA inhibitor. Image analysis showed there was more PPAR-α in the nucleus with 8-Br-cAMP treatment, and less PPAR-α in the nucleus with RPCA treatment. Therefore, PKA is involved in regulating PPAR-α (VEH, 1194±74; 8-Br-cAMP, 1490±44; RPCA, 740±75; 8-Br-cAMP+ RPCA, 1037±54; VEH vs 8-Br-cAMP, P<0.01; 8-Br-cAMP vs 8-Br-cAMP+ RPCA, P<0.001; one-way ANOVA, n=13). Moreover, gastrin mRNA was increased by 8-Br-cAMP stimulation while the increase was blocked by RPCA (VEH, 1.01±0; 8-Br-cAMP, 1.32±0.07; RPCA, 0.82±0.08; 8-Br-cAMP+ RPCA, 0.9±0.05; VEH vs 8-Br-cAMP, P<0.05; 8-Br-cAMP vs 8-Br-cAMP+ RPCA, p<0.01; one-way ANOVA, n=3). Gastrin protein level was also increased by 8-Br-cAMP treatment with image analysis (VEH, 1.14±0.01; 8-Br-cAMP, 1.28±0.01; RPCA, 1.17±0.01; 8-Br-cAMP+ RPCA, 1.38±0.03; VEH vs 8-Br-cAMP, P<0.01; one-way ANOVA, n=3). These data indicate that PKA is involved in the D 1 R and PPAR-α pathways to regulate G-cell gastrin expression stimulated by sodium.