The three core feedback pathways of the (anterior) pituitary gland cell model. Illustration of the intracellular pathways of the extended HPA model of Figure2 showing the three main feedback mechanisms (with respect to the involved receptors) in the anterior pituitary gland cells. A) Genomic pathway of the GR mediated feedback: Outline of the modeled species involved in the inhibition of POMC (Proopiomelanocortin) transcription which corresponds to the inhibition of ACTH production. ACTH is obtained via post-translational cleavaging of the POMC protein. The central transcription factor is the GR-cortisol complex which down regulates the POMC transcription and enhances the production of the GR receptor. B) Non-genomic pathway of the GPCR mediated feedback: The non-genomic negative feedback mechanism via the glucocorticoid membrane receptor GPCR, inhibiting the release of ACTH. C) CRHR mediated feedback: The positive feedback mechanisms associated with the CRH membrane receptor (CRHR), which causes an increased release of ACTH from vesicles and an increased expression of the POMC gene.