Abstract
Somatostatin (SST) 14 and SST 28 activate somatostatin 2A receptors (SSTR2A) on enteric neurons to control gut functions. SST 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 SSTR2A is unexplored. We evaluated SSTR2A 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 SSTR2A trafficking and association with β-arrestins, key regulators of receptors. SST-14, SST-28, and peptide analogs (octreotide, lanreotide, and vapreotide) stimulated clathrin- and dynamin-mediated internalization of SSTR2A, which colocalized with ECE-1 in endosomes and the Golgi. After incubation with SST-14, SSTR2A recycled to the plasma membrane, which required active ECE-1 and an intact Golgi. SSTR2A activated by SST-28, octreotide, lanreotide, or vapreotide was retained within the Golgi and did not recycle. Although ECE-1 rapidly degraded SST-14, SST-28 was resistant to degradation, and ECE-1 did not degrade SST analogs. SST-14 and SST-28 induced transient interactions between SSTR2A and β-arrestins that were stabilized by an ECE-1 inhibitor. Octreotide induced sustained SSTR2A/β-arrestin interactions that were not regulated by ECE-1. Thus, when activated by SST-14, SSTR2A internalizes and recycles via the Golgi, which requires ECE-1 degradation of SST-14 and receptor dissociation from β-arrestins. After activation by ECE-1-resistant SST-28 and analogs, SSTR2A remains in endosomes because of sustained β-arrestin interactions. Therapeutic SST analogs are ECE-1-resistant and retain SSTR2A in endosomes, which may explain their long-lasting actions.
Highlights
Somatostatin regulates gut function via neuronal somatostatin receptors
We evaluated SSTR2A 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 SSTR2A trafficking and association with -arrestins, key regulators of receptors
Agonists Variably Stimulate Clathrin- and Dynamin-dependent Endocytosis of SSTR2A in Myenteric Neurons—We examined the effects of endogenous agonists (SST-14 and SST-28), octapeptide analogs, and a non-peptide agonist (L-054,264) on the subcellular distribution of SSTR2A in myenteric neurons
Summary
Somatostatin regulates gut function via neuronal somatostatin receptors. Results: Somatostatin susceptibility to degradation by endosomal endothelin-converting enzyme 1 (ECE-1) defines receptor function. We evaluated SSTR2A 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 SSTR2A trafficking and association with -arrestins, key regulators of receptors. Endosomal peptidases (e.g. endothelin-converting enzyme 1, ECE-1) degrade neuropeptides in endosomes, which disassembles signalosomes, terminates endosomal signaling, and promotes receptor recycling and resensitization of plasma membrane signaling [3] These processes are key regulators of peptide signaling. Stable SST analogs (e.g. octreotide) are effective treatments for acromegaly, diarrhea, bleeding disorders, and cancer, and radiolabeled agonists can be used to detect neuroendocrine tumors [4] These drugs have side effects related to their actions on the gastrointestinal tract, including constipation, abdominal cramps, and nausea [4]. Resistance to extracellular proteolysis is important for development of SST analogs, resistance to intracellular proteolysis is a key determinant of their longlasting therapeutic and side effects
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