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No ligand needed for learning
In addition to its role in stimulating appetite, the hormone ghrelin and its receptor GHS-R1a are implicated in cognition. Ribeiro et al. found a role for ghrelin-independent GHS-R1a signaling in learning in mice. The use of inverse agonists and mutants revealed that ligand-independent activity of GHS-R1a maintained the synaptic abundance of AMPA-type glutamate receptors in hippocampal neurons through a phosphorylation-dependent trafficking mechanism in cultured neurons and brain slices, thereby ensuring tonic control of synaptic plasticity. Treating mice with a GHS-R1a inverse agonist impaired spatial and contextual memory formation. Thus, the use of ghrelin receptor–blocking therapies—which have been proposed for treating metabolic disorders, acromegaly, cancer, and alcoholism—may also have cognitive side effects.
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