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

Diabetologia. 2015 Oct;58(10):2298-306. doi: 10.1007/s00125-015-3683-8. Epub 2015 Jul 4.


Aims/hypothesis: 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/interpretation: 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.

Keywords: Cav1.2; IA-2; Insulin secretion; Intronic miRNA; MicroRNAs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Brain / metabolism
  • Calcium Channels, L-Type / genetics
  • Calcium Channels, L-Type / metabolism*
  • Cell Line
  • Dopamine / metabolism*
  • Gene Expression Regulation
  • Glucose / metabolism
  • Insulin / metabolism*
  • Islets of Langerhans / metabolism
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Pancreas / metabolism
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8 / genetics
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8 / metabolism


  • CACNA1C protein, mouse
  • Calcium Channels, L-Type
  • Insulin
  • MIRN153 microRNA, mouse
  • MicroRNAs
  • Ptprn protein, mouse
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8
  • Glucose
  • Dopamine