A G Protein-Coupled Receptor Dimerization Interface in Human Cone Opsins

G protein-coupled receptors (GPCRs) detect a wide variety of physical and chemical signals and transmit that information across the cellular plasma membrane. Dimerization is a proposed modulator of GPCR signaling, but the structure and stability of class A GPCR dimerization have been difficult to establish. Here we investigated the dimerization affinity and binding interface of human cone opsins, which initiate and sustain daytime color vision. Using a time-resolved fluorescence approach, we found that human red cone opsin exhibits a strong propensity for dimerization, whereas the green and blue cone opsins do not. Through mutagenesis experiments, we identified a dimerization interface in the fifth transmembrane helix of human red cone opsin involving amino acids I230, A233, and M236. Insights into this dimerization interface of red cone opsin should aid ongoing investigations of the structure and function of GPCR quaternary interactions in cell signaling. Finally, we demonstrated that the same residues needed for dimerization are also partially responsible for the spectral tuning of red cone opsin. This last observation has the potential to open up new lines of inquiry regarding the functional role of dimerization for red cone opsin

First metatarsophalangeal joint arthrodesis versus proximal phalanx hemiarthroplasty for hallux rigidus: feasibility study for a randomised controlled trial

BACKGROUND: Osteoarthritis of the first metatarsophalangeal joint (hallux rigidus) leads to pain and poor function and mobility. Arthrodesis is the gold standard treatment for end-stage disease. Total joint arthroplasties have been attempted, but early loosening has been attributed to dorsally directed shear forces on the metatarsal component. Metallic proximal phalangeal hemiarthroplasty theoretically avoids this. Whilst early results are promising, no comparative trials exist comparing this to arthrodesis. METHODS/DESIGN: The primary objectives are to determine the range of outcome scores between the two treatment arms (to inform a power calculation). Outcome measures will include the MOXFQ, AOFAS-Hallux and EuroQol EQ-5D-5 L. Secondary objectives are to determine the accrual rate, dropout rate and trial acceptability to both patients and surgeons. These data will allow the development of a larger trial with longer follow-up.This is a prospective randomised controlled single-centre study comparing proximal phalanx hemiarthroplasty (AnaToemic, Arthrex Ltd., Sheffield, UK) with arthrodesis (15 patients in each arm). Randomisation will be performed using a 1:1 allocation ratio in blocks of six.Patients meeting the eligibility criteria will be recruited from three foot and ankle consultant surgeon's clinics (East Lancashire Hospitals NHS Trust). If agreeable, informed consent will be obtained before patients are randomised.The outcome measure scores will be completed pre-operatively and repeated at 6 weeks, 3 months and 12 months. A radiological review will be performed at 6 weeks and 12 months to determine rates of loosening (hemiarthroplasty) and union (arthrodesis). Data on length of stay, return to work, complications and re-operation rates will also be collected.The analysis will compare the change in outcome scores between treatment groups at all follow-up time points. Scores will be compared using a Student t-test, adjusting for scores at baseline.This study will be conducted in accordance with the current revision of the Declaration of Helsinki (1996) and the ICH-GCP Guideline (International Conference on Harmonisation, Good Clinical Practice, E6(R1), 1996). This study has been approved by the sponsor, the Trust Research and Development office. Ethical approval has been received from the National Research Ethics Service (North East: 12/NE/0385 for protocol version 5.3 dated 3 June 2013). TRIAL REGISTRATION: Current Controlled Trials ISRCTN88273654