title: The Ia-2β intronic miRNA, miR-153, is a negative regulator of insulin and dopamine secretion through its effect on the Cacna1c gene in mice.
abstract: OBJECTIVE
  miR-153 is an intronic miRNA embedded in the genes that encode IA-2 (also known as PTPRN) and IA-2β (also known as PTPRN2). Islet antigen (IA)-2 and IA-2β are major autoantigens in type 1 diabetes and are important transmembrane proteins in dense core and synaptic vesicles. miR-153 and its host genes are co-regulated in pancreas and brain. The present experiments were initiated to decipher the regulatory network between miR-153 and its host gene Ia-2β (also known as Ptprn2).
  
  
  METHODS
  Insulin secretion was determined by ELISA. Identification of miRNA targets was assessed using luciferase assays and by quantitative real-time PCR and western blots in vitro and in vivo. Target protector was also employed to evaluate miRNA target function.
  
  
  RESULTS
  Functional studies revealed that miR-153 mimic suppresses both glucose- and potassium-induced insulin secretion (GSIS and PSIS, respectively), whereas miR-153 inhibitor enhances both GSIS and PSIS. A similar effect on dopamine secretion also was observed. Using miRNA target prediction software, we found that miR-153 is predicted to target the 3'UTR region of the calcium channel gene, Cacna1c. Further studies confirmed that Cacna1c mRNA and protein are downregulated by miR-153 mimics and upregulated by miR-153 inhibitors in insulin-secreting freshly isolated mouse islets, in the insulin-secreting mouse cell line MIN6 and in the dopamine-secreting cell line PC12.
  
  
  CONCLUSIONS
  miR-153 is a negative regulator of both insulin and dopamine secretion through its effect on Cacna1c expression, which suggests that IA-2β and miR-153 have opposite functional effects on the secretory pathway.
authors.affiliation: Experimental Medicine Section, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892, USA.
authors.forename: Huanyu
authors.initials: H
authors.lastname: Xu
authors.affiliation: Experimental Medicine Section, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892, USA.
authors.forename: Liron
authors.initials: L
authors.lastname: Abuhatzira
authors.affiliation: Experimental Medicine Section, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892, USA.
authors.forename: Gilberto N
authors.initials: GN
authors.lastname: Carmona
authors.affiliation: Brehm Diabetes Research Center, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Suryakiran
authors.initials: S
authors.lastname: Vadrevu
authors.affiliation: Brehm Diabetes Research Center, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Satin
authors.affiliation: Experimental Medicine Section, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892, USA. anotkins@dir.nidcr.nih.gov.
authors.forename: Abner L
authors.initials: AL
authors.lastname: Notkins
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004298:Dopamine / Q000378:metabolism*; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000235:genetics / Q000378:metabolism
chemical_list: C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; D007328:Insulin; C577878:MIRN153 microRNA, mouse; D035683:MicroRNAs; C516863:Ptprn protein, mouse; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005947:Glucose; D004298:Dopamine
keywords: Cav1.2; IA-2; Insulin secretion; Intronic miRNA; MicroRNAs