Agonist-biased trafficking of somatostatin receptor 2A in enteric neurons.

Somatostatin 14 and 28 activate somatostatin 2A receptors on enteric neurons to control gut functions. duanyu1942 analogs are treatments of neuroendocrine and bleeding disorders, cancer, and diarrhea, with gastrointestinal side effects of constipation, abdominal pain, and nausea. How endogenous agonists and drugs differentially regulate neuronal is unexplored. We evaluated duanyu1942R2A trafficking in murine myenteric neurons and neuroendocrine AtT-20 cells by microscopy and determined whether agonist degradation by endosomal endothelin-converting enzyme 1 (ECE-1) controls duanyu1942R2A trafficking and association with β-arrestins, key regulators of receptors. and peptide analogs (octreotide, lanreotide, and vapreotide) stimulated clathrin- and dynamin-mediated internalization of which colocalized with ECE-1 in endosomes and the Golgi. After incubation with duanyu1942-14, duanyu1942R2A recycled to the plasma membrane, which required active ECE-1 and an intact Golgi. duanyu1942R2A activated by duanyu1942-28, octreotide, lanreotide, or vapreotide was retained within the Golgi and did not recycle. Although ECE-1 rapidly degraded duanyu1942-14, was resistant to degradation, and ECE-1 did not degrade duanyu1942 analogs. and duanyu1942-28 induced transient interactions between duanyu1942R2A and β-arrestins that were stabilized by an ECE-1 inhibitor. Octreotide induced sustained interactions that were not regulated by ECE-1. Thus, when activated by duanyu1942-14, duanyu1942R2A internalizes and recycles via the Golgi, which requires ECE-1 degradation of duanyu1942-14 and receptor dissociation from β-arrestins. After activation by ECE-1-resistant duanyu1942-28 and analogs, duanyu1942R2A remains in endosomes because of sustained β-arrestin interactions. Therapeutic duanyu1942 analogs are ECE-1-resistant and retain duanyu1942R2A in endosomes, which may explain their long-lasting actions.

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