Structural basis for recognition of anti-migraine drug lasmiditan by the serotonin receptor 5-HT1F-G protein complex

Migraine headache has become global pandemics and is the number one reason of work day loss. The most common drugs for anti-migraine are the triptan class of drugs that are agonists for serotonin receptors 5-HT1B and 5-HT1D. However, these drugs have side effects related to vasoconstriction that could have fatal consequences of ischemic heart disease and myocardial infarction. Lasmiditan is a new generation of anti-migraine drug that selectively binds to the serotonin receptor 5-HT1F due to its advantage over the tripan class of anti-migraine drugs. Here we report the cryo-EM structure of the 5-HT1F in complex with Lasmiditan and the inhibitory G protein heterotrimer. The structure reveals the mechanism of 5-HT1F-selective activation by Lasmiditan and provides a template for rational design of anti-migraine drugs.

EP3 signaling is decoupled from regulation of glucose-stimulated insulin secretion in β-cells compensating for obesity and insulin resistance

ABSTRACTOf the β-cell signaling pathways altered by non-diabetic obesity and insulin resistance, some are adaptive while others actively contribute to β-cell failure and demise. Cytoplasmic calcium (Ca2+) and cyclic AMP (cAMP), which control the timing and amplitude of insulin secretion, are two important signaling intermediates that can be controlled by stimulatory and inhibitory G protein-coupled receptors. Previous work has shown the importance of the cAMP-inhibitory EP3 receptor in the beta-cell dysfunction of type 2 diabetes. To examine alterations in β-cell cAMP during diabetes progression we utilized a β-cell specific cAMP biosensor in tandem with islet Ca2+ recordings and insulin secretion assays. Three groups of C57BL/6J mice were used as a model of the progression from metabolic health to type 2 diabetes: wildtype, normoglycemic LeptinOb, and hyperglycemic LeptinOb. Here, we report robust increases in β-cell cAMP and insulin secretion responses in normoglycemic Leptinob mice as compared to wild-type: an effect that was lost in islets from hyperglycemic Leptinob mice, despite elevated Ca2+ duty cycle. Yet, the correlation of EP3 expression and activity to reduce cAMP levels and Ca2+ duty cycle with reduced insulin secretion only held true in hyperglycemic LeptinOb mice. Our results suggest alterations in beta-cell EP3 signaling may be both adaptive and maladaptive and define β-cell EP3 signaling as much more nuanced than previously understood.