Dietary sodium stimulates the renal excretion of sodium long before there is expansion of the extracellular fluid volume. We have previously shown that an increase in sodium concentration in the incubation buffer in human SW626 colon adenocarcinoma cells that express gastrin-secreting G- cells increased gastrin mRNA and protein. Thus, we hypothesized that increasing extracellular sodium would also increase gastrin expression in normal human stomach G-cells. The highest sodium concentration (170 mM) increased gastrin protein expression significantly (all cell lines were normalized to their gastrin expression at 90 mM, sodium). In normal human G-cells cultured in non-polarized conditions, the normalized gastrin expression in cells incubated in 143mM sodium was 0.98 ± 0.06; 170mM sodium increased gastrin expression 1.515 ± 0.106-fold (n=4 different cell lines, P<0.01 one-way ANOVA). Cultured human renal tubule cells demonstrate more physiologically relevant phenotype when grown in a 3D cell culture (3DCC) system. Therefore, we also studied human G-cells grown in 3DCC. Normal human G-cells grown in 3D also had a greater gastrin expression when incubated in 170 than143 mM sodium: 1.08 ± 0.12 vs. 0.62 ± 0.04, n=4, P<0.05, t-test). We have also shown that the dopamine type 1 receptor (D 1 R) is expressed in G-cells and may play a role in regulation of gastrin expression. We now report the presence of the complete dopamine biosynthetic pathway in human G-cells: tyrosine hydroxylase is expressed ubiquitously in the stomach while DOPA decarboxylase is expressed selectively in G-cells where D 1 R is also expressed. We have reported that in the kidney, gastrin, via CCKBR and dopamine, via D 1 R synergistically increase renal sodium excretion. Thus, the pathway that is involved in the increase in sodium excretion after the ingestion sodium involves sodium- and D 1 R-mediated increase in gastrin expression in G-cells, followed by secretion of gastrin into the circulation to interact with kidney mediated gastrin pathways.