SUMMARYThe essential role for phosphatidylinositol 4-phosphate (PtdIns[4]P) in vesicle-mediated protein transport from the trans-Golgi network (TGN) was first described in budding yeast1–3. However, the identity of downstream effectors of PtdIns[4]P in this system has been elusive. Here, we show that Drs2p, a type IV P-type ATPase required for phospholipid translocase (flippase) activity and transport vesicle budding from the TGN4–8, is an effector of PtdIns[4]P. Drs2p-dependent flip of a fluorescent phosphatidylserine analogue across purified TGN membranes requires synthesis of PtdIns[4]P by the PtdIns 4-kinase Pik1p. PtdIns[4]P binds to a regulatory domain in the C-terminal tail of Drs2p that has homology to a split PH domain and is required for Drs2p activity. In addition, basic residues required for phosphoinositide binding overlap a binding site for the ArfGEF Gea2p that was previously mapped9. ArfGEF binding to this C-terminal domain also stimulates flippase activity in TGN membrane preparations. These interactions imply the presence of a novel coincidence detection system used to activate phospholipid translocation at sites of vesicle formation.

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The authors investigated whether patients receiving buprenorphine maintenance treatment (BMT) will have corrected QT (QTc) prolongation after taking buprenorphine for an extended period of time. They also compared QTc prolongation for patients in methadone maintenance treatment (MMT) versus BMT to determine which medication is the better option for patients with heart disease. A retrospective chart review study of 73 patients in BMT and 55 patients in MMT was performed. A linear regression model with a one-sided P value was used for data analysis. The MMT group had statistically significant prolongation of QTc compared with the BMT group (F = 3.94, P = .0001). Being diagnosed with congestive heart failure and taking methadone were the only individual variables that showed a statistically significant association with a QTc prolongation > 500 ms. The model as a whole showed statistical significance (F = 5.203, P = .007). Being diagnosed with congestive heart failure was the only individual variable that showed a statistically significant association with mortality. The model as a whole also showed statistical significance (F = 17.15, P = .000). This study supports previous findings that methadone may be associated with QTc prolongation, whereas buprenorphine may not. This study has the advantage of confirming that QTc prolongation persists in patients in MMT but not in those in BMT over an extended period of time (i.e., 5 years). Buprenorphine might a better first-line opioid maintenance treatment for patients with heart disease because buprenorphine was not associated with QTc prolongation. Patients in BMT may not need to be screened routinely for QTc prolongation.

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