CMAJ 2007;176(8):1113-20

No abstract

Serotonin (5-HT) interacts with a wide variety of 5-HT receptors (5-HTR) of which 5-HT 2A R plays an important target for antidepressant and atypical antipsychotic drugs. The carboxyl-terminal tail of 5-HT 2A R encodes a motif that mediates interactions with PSD-95/disc large/zona occludens (PDZ) domain-containing proteins. In the present study, we found that 5-HT 2A R interacts with synapse-associated protein 97 (SAP97; also known as DLG1) by coimmunoprecipitation in human embryonic 293 (HEK 293) cells and cortical brain lysates. We found that 5-HT 2A R expression results in the recruitment of SAP97 from the cytosol to the plasma membrane and that this recruitment is dependent on an intact 5-HT 2A R PDZ binding motif. We also show that 5-HT 2A R interacts with SAP97 using bioluminescence energy transfer and that overexpression of SAP97 retards 5-HT 2A R endocytosis, Similarly to what has been observed for the corticotropinreleasing factor receptor 1 (CRFR1), SAP97 expression is essential for 5-HT 2A R-stimulated extracellular-regulated protein kinase 1/2 (ERK1/2) phosphorylation by a PDZ interactionindependent mechanism. Moreover, we find that SAP97 is not responsible for CRFR1-mediated sensitization of 5-HT 2A R signaling. Taken together, our studies show that SAP97 plays a conserved role in regulating 5-HT 2A R endocytosis and ERK1/2 signaling, but plays a novel role in regulating 5-HT 2A R G protein coupling.

No abstract

A well-worn medical aphorism states that "when you hear hoof beats, think of a horse and not a zebra." When applying this principle to the cardiometabolic syndrome (CMS), the horse would be represented by the prevalent CMS phenotype that affects approximately 30% of individuals in Westernized societies, while the zebra is represented by very rare conditions--such as lipodystrophy syndromes--that share some features with the more prevalent CMS. For instance, familial partial lipodystrophy types 2 and 3 result from heterozygous mutations in LMNA, encoding nuclear lamin A/C, and in PPARG, encoding peroxisome proliferator-activated receptor (PPAR)-gamma, respectively. Patients with either subtype of partial lipodystrophy exhibit an increased ratio of central to peripheral fat stores, dysglycemia, dyslipidemia, and hypertension, with predisposition for developing insulin-resistant diabetes and atherosclerosis end points. Sometimes, however, the zebra serves as a model that can help us understand the horse, so that the rare partial lipodystrophies might offer some insight into pathogenesis and treatment of the more prevalent CMS.