Dopamine Not Making the Pancreas Happy?

Dopamine Not Making the Pancreas Happy?

Hikari Tanaka

The word “dopamine” brings to mind a few key ideas, such as the brain, reward and motor pathways, and common neurological disorders such as Parkinson’s Disease and schizophrenia. But this neurotransmitter also appears to play a role in inhibiting insulin secretion from the pancreatic beta cells as well. 

The Dopamine Receptor Fam

There are five dopamine receptors, D1 through D5, which are all G-protein coupled receptors. While they are from different chromosomal loci, a few of them share homology with each other in terms of their protein shape and function6. The ones key to pancreatic beta cells are D2, D3 and D4 (together dubbed “D2-like receptors), which seem to inhibit adenylate cyclase activity 1,9. Adenylyl cyclase catalyzes the conversion of ATP to cAMP and interestingly, the cAMP activator Forskolin can prevent dopamine’s inhibitory effects too8

The dopamine receptors may allow dopamine to take part in a negative, auto-paracrine feedback loop to shut down insulin secretion. By adding various concentrations of dopamine in vitro, insulin secretion has been found to be severely inhibited3. In the same study, dopamine stopped the proliferation and increased apoptosis (through the increase of caspase-3) of the pancreatic beta cells. These effects could be reversed through a D2 receptor antagonist though. Domperidone (DPD) is an antagonist that can prevent apoptosis and dedifferentiation of the beta cells, and knockdowns of the D2 receptor can present the same effects6. Let’s talk more about this interesting dopamine receptor.

D2-like Receptors: The Culprit?

The connections between T1D and neuroscience only seems to grow! When beta cells sense high glucose concentrations, ATP levels increase and also cause depolarization, which in turn causes calcium influx and insulin release4. Key ion channels can impede this effect via dopamine binding, such as via the D2-like receptors. When D2-like receptors are activated by high glucose, this can decrease intracellular calcium and in turn, inhibit insulin release5.  Furthermore, the adenylyl cyclase, cAMP, and protein kinase A pathway may also play a role in this voltage-gated ion channel network.

Freshly Made L-Dopa in the Beta Cells  

Pancreatic beta cells can also make dopamine; glucose can cause beta cells to uptake and process L-dopa2, the precursor to dopamine, which can then inhibit glucose-stimulated insulin release via the D2 and D3 receptors. When the two receptors are knocked out, less dopamine is secreted after glucose stimulation. So just as with everything in science, another wrench is thrown into the complicated dopamine and insulin secreting pathway of the pancreatic beta cells. While it is more complicated with this newfound knowledge, it will bring us one step closer to developing effective treatment options for T1D patients.

Main takeaway: Pancreatic beta cells have dopaminergic receptors, which can respond to glucose stimulation to decrease insulin release.

Sources

  1. Enjalbert A FAU – Bockaert, J, & Bockaert, J.Pharmacological characterization of the D2 dopamine receptor negatively coupled with adenylate cyclase in rat anterior pituitary
  2. Farino, Z. J., Morgenstern, T. J., Maffei, A., Quick, M., De Solis, A.,J., Wiriyasermkul, P., . . . Freyberg, Z. (2019). New roles for dopamine D(2) and D(3) receptors in pancreatic beta cell insulin secretion. Molecular Psychiatry, , 10.1038/s41380-018-0344-6. doi:10.1038/s41380-018-0344-6
  3. Garcia Barrado, M. J., Iglesias Osma, M. C., Blanco, E. J., Carretero Hernández, M., Sánchez Robledo, V., Catalano Iniesta, L., . . . Carretero, J. (2015). Dopamine modulates insulin release and is involved in the survival of rat pancreatic beta cells. PloS One, 10(4), e0123197-e0123197. doi:10.1371/journal.pone.0123197
  4. Jacobson, D. A., & Philipson, L. H. (2007). Action potentials and insulin secretion: New insights into the role of kv channels. Diabetes, Obesity and Metabolism, 9, 89-98. doi:10.1111/j.1463-1326.2007.00784.x
  5. Liu, M., Ren, L., Zhong, X., Ding, Y., Liu, T., Liu, Z., . . . Zhang, Y. (2020). D2-like receptors mediate dopamine-inhibited insulin secretion via ion channels in rat pancreatic β-cells. Frontiers in Endocrinology, 11, 152.
  6. Missale, C., W,Nash SR FAU – Robinson, S., M,Robinson SW FAU – Jaber, Jaber M FAU – Caron,,M.G., & Caron, M. G.Dopamine receptors: From structure to function
  7. Sakano, D., Choi, S., Kataoka, M., Shiraki, N., Uesugi, M., Kume, K., & Kume, S. (2016). Dopamine D2 receptor-mediated regulation of pancreatic β cell mass. Stem Cell Reports, 7(1), 95-109. doi:10.1016/j.stemcr.2016.05.015
  8. Shankar, E., Santhosh, K. T., & Paulose Director, C. S. (2006). Dopaminergic regulation of glucose-induced insulin secretion through dopamine D2 receptors in the pancreatic islets in vitro. IUBMB Life, 58(3), 157-163. doi:10.1080/15216540600687993
  9. Ustione, A., Piston, D. W., & Harris, P. E. (2013). Minireview: Dopaminergic regulation of insulin secretion from the pancreatic islet. Molecular Endocrinology (Baltimore, Md.), 27(8), 1198-1207. doi:10.1210/me.2013-1083

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