Identification of emergency department patients for referral to rapid-access addiction services.

OBJECTIVES: Substance-related emergency department (ED) visits are rapidly increasing. Despite this finding, many EDs do not have access to on-site addiction services. This study characterized substance-related ED presentations and assessed the ED health care team's perceived need for an on-site rapid-access addiction clinic for direct patient referral from the ED. METHODS: This prospectively enrolled cohort study was conducted at an urban tertiary care ED from June to August 2018. Adult ED patients with problematic or high-risk substance use were enrolled by ED staff using a one-page form. The electronic and paper records from the index ED visit were reviewed. The primary outcome evaluated whether the ED health care team would have referred the patient to an on-site rapid-access addiction clinic, if one were available. RESULTS: We received 557 enrolment forms and 458 were included in the analysis. Median age was 35 years, and 64% of included patients were male. Alcohol was the most commonly reported substance of problematic or high-risk use (60%). Previous ED visits within 7 days of the index visit were made by 28% of patients. The ED health care team indicated "Yes" for rapid-access addiction clinic referral from the ED for 66% of patients, with a mean of 4.3 patients referred per day during the study period. CONCLUSIONS: At least four patients per day would have been referred to an on-site rapid-access addiction clinic from the ED, had one been available. This indicates a gap in care and collaborating with other sites that have successfully implemented this clinic model is an important next step.

Erratum: PRL3 phosphatase active site is required for binding the putative magnesium transporter CNNM3.

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

PRL3 phosphatase active site is required for binding the putative magnesium transporter CNNM3.

The phosphatases of regenerating liver (PRLs) are involved in tumorigenesis and metastatic cancer yet their cellular function remains unclear. Recent reports have shown PRL phosphatases bind tightly to the CNNM family of membrane proteins to regulate magnesium efflux. Here, we characterize the interactions between the CBS-pair (Bateman) domain of CNNM3 and either PRL2 or PRL3 using X-ray crystallography, isothermal titration calorimetry, and activity assays. We report four new crystal structures of PRL proteins bound to the CNNM3 CBS-pair domain that reveal the effects of cysteine disulphide formation and nucleotide binding on complex formation. We use comprehensive mutagenesis of the PRL3 catalytic site to quantify the importance of different PRL amino acids, including cysteine 104, leucine 108, and arginine 110, for CNNM binding and phosphatase activity. We show the PRL3 R138E mutant is selectively deficient in CNNM3 binding with the potential to distinguish between the downstream effects of phosphatase and CNNM-binding activities in vivo. Through a novel activity assay, we show that PRL3 has magnesium-sensitive phosphatase activity with ATP and other nucleotides. Our results identify a strong correlation between phosphatase activity and CNNM binding and support the contention that PRL function as pseudophosphatases regulated by chemical modifications of their catalytic cysteine.

Phosphocysteine in the PRL-CNNM pathway mediates magnesium homeostasis.

PRLs (phosphatases of regenerating liver) are frequently overexpressed in human cancers and are prognostic markers of poor survival. Despite their potential as therapeutic targets, their mechanism of action is not understood in part due to their weak enzymatic activity. Previous studies revealed that PRLs interact with CNNM ion transporters and prevent CNNM4-dependent Mg2+ transport, which is important for energy metabolism and tumor progression. Here, we report that PRL-CNNM complex formation is regulated by the formation of phosphocysteine. We show that cysteine in the PRL catalytic site is endogenously phosphorylated as part of the catalytic cycle and that phosphocysteine levels change in response to Mg2+ levels. Phosphorylation blocks PRL binding to CNNM Mg2+ transporters, and mutations that block the PRL-CNNM interaction prevent regulation of Mg2+ efflux in cultured cells. The crystal structure of the complex of PRL2 and the CBS-pair domain of the Mg2+ transporter CNNM3 reveals the molecular basis for the interaction. The identification of phosphocysteine as a regulatory modification opens new perspectives for signaling by protein phosphatases.