Dopamine D1 Receptor Signaling for Steroidogenic Differentiation


Induced pluripotent stem cells are a powerful tool for investigating the molecular mechanisms that underlie cell development in vitro. A November 2017 paper by Matsuo et al. examined the process of steroidogenic differentiation using human stem cell derived intermediate mesoderm cells known to be the origin of human adrenal cortex and gonads. Through screening they identified cabergoline as a small molecule inducer of 3β-hydroxysteroid dehydrogenase, an essential enzyme for steroidogenesis in adrenogonadal cells. Cabergoline is a dopamine D2 receptor agonist that also has low-affinity activity on dopamine D1 receptors. Further experimentation showed the D1 agonist activity increased cAMP thereby activating PKA and was key for inducing steroidogenesis. Concerned that the intermediate cells were not mature enough to observe the full extent of the dopamine receptor agonists, they moved forward to using OSR1+ cells transfected to express steroidogenic factor-1/adrenal 4 binding protein. With those transfected cells they proved that dopamine D1 receptor agonists upregulated the expression of a variety of steroidogenic enzymes and ultimately measured increased secretion of stress steroid cortisol (Arbor Assays, K003-H).

Previous studies have focused on the function of D2 receptors in the adrenal cortex and have perhaps overlooked the role D1 receptors play, especially during differentiation into steroid secreting cells. While there is still more to learn about the precise mechanisms through which D1 receptors influence adrenal development and steroidogenesis, the method described in the Matsuo paper offers an improvement in method for differentiating steroid producing cells as well as a better understanding of the native processes occurring in vitro during fetal development. Production of such cells offers insight into the mechanisms affected by diseases that cause adrenal insufficiency and therefore the potential to develop treatments to prevent them. The ability to reliably generate steroid producing cells from an individual’s own stems cells also offers the opportunity for permanent treatment for those individuals already suffering from adrenal deficiencies, especially glucocorticoid insufficiency, which can be fatal. Currently these patients require treatment with exogenous steroids for the rest of their lives and are always at risk from side effects including adrenal crisis, obesity, osteoporosis, hypertension and glucose intolerance.

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