title: The expression and function of histamine H₃ receptors in pancreatic beta cells.
abstract: OBJECTIVE
  Histamine and its receptors in the CNS play important roles in energy homeostasis. Here, we have investigated the expression and role of histamine receptors in pancreatic beta cells, which secrete insulin.
  
  
  METHODS
  The expression of histamine receptors in pancreatic beta cells was examined by RT-PCR, Western blotting and immunostaining. Insulin secretion assay, ATP measurement and calcium imaging studies were performed to determine the function and signalling pathway of histamine H₃ receptors in glucose-induced insulin secretion (GIIS) from MIN6 cells, a mouse pancreatic beta cell line. The function and signalling pathway of H₃ receptors in MIN6 cell proliferation were examined using pharmacological assay and Western blotting.
  
  
  RESULTS
  Histamine H₃ receptors were expressed in pancreatic beta cells. A selective H₃ receptor agonist, imetit, and a selective inverse H₃ receptor agonist, JNJ-5207852, had inhibitory and facilitatory effects, respectively, on GIIS in MIN6 cells. Neither imetit nor JNJ-5207852 altered intracellular ATP concentration, or intracellular calcium concentration stimulated by glucose and KCl, indicating that GIIS signalling was affected by H3 receptor signalling downstream of the increase in intracellular calcium concentration. Moreover, imetit attenuated bromodeoxyuridine incorporation in MIN6 cells. The phosphorylation of cAMP response element-binding protein (CREB), which facilitated beta cell proliferation, was inhibited, though not significantly, by imetit, indicating that activated H₃ receptors inhibited MIN6 cell proliferation, possibly by decreasing CREB phosphorylation.
  
  
  CONCLUSIONS
  Histamine H₃ receptors were expressed in mouse beta cells and could play a role in insulin secretion and, possibly, beta cell proliferation.
authors.affiliation: Department of Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nakamura
authors.forename: T
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: N
authors.initials: N
authors.lastname: Noguchi
authors.forename: A
authors.initials: A
authors.lastname: Sugawara
authors.forename: A
authors.initials: A
authors.lastname: Kasajima
authors.forename: H
authors.initials: H
authors.lastname: Sasano
authors.forename: K
authors.initials: K
authors.lastname: Yanai
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D054314:Drug Inverse Agonism; D005947:Glucose / Q000378:metabolism; D017442:Histamine Agonists / Q000494:pharmacology; D006633:Histamine Antagonists / Q000494:pharmacology; D006640:Histidine Decarboxylase / Q000172:deficiency / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D010766:Phosphorylation; D018100:Receptors, Histamine H3 / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D017442:Histamine Agonists; D006633:Histamine Antagonists; D007328:Insulin; D018100:Receptors, Histamine H3; D000255:Adenosine Triphosphate; D006640:Histidine Decarboxylase; D005947:Glucose
keywords: histamine H3 receptor; insulin secretion; pancreatic beta cells