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The β1-adrenoceptor (β1AR) is a G-protein-coupled receptor (GPCR) that couples1 to the heterotrimeric G protein Gs. G-protein-mediated signalling is terminated by phosphorylation of the C terminus of the receptor by GPCR kinases (GRKs) and by coupling of β-arrestin 1 (βarr1, also known as arrestin 2), which displaces Gs and induces signalling through the MAP kinase pathway2. The ability of synthetic agonists to induce signalling preferentially through either G proteins or arrestins-known as biased agonism3-is important in drug development, because the therapeutic effect may arise from only one signalling cascade, whereas the other pathway may mediate undesirable side effects4. To understand the molecular basis for arrestin coupling, here we determined the cryo-electron microscopy structure of the β1AR-βarr1 complex in lipid nanodiscs bound to the biased agonist formoterol5, and the crystal structure of formoterol-bound β1AR coupled to the G-protein-mimetic nanobody6 Nb80. βarr1 couples to β1AR in a manner distinct to that7 of Gs coupling to β2AR-the finger loop of βarr1 occupies a narrower cleft on the intracellular surface, and is closer to transmembrane helix H7 of the receptor when compared with the C-terminal α5 helix of Gs. The conformation of the finger loop in βarr1 is different from that adopted by the finger loop of visual arrestin when it couples to rhodopsin8. β1AR coupled to βarr1 shows considerable differences in structure compared with β1AR coupled to Nb80, including an inward movement of extracellular loop 3 and the cytoplasmic ends of H5 and H6. We observe weakened interactions between formoterol and two serine residues in H5 at the orthosteric binding site of β1AR, and find that formoterol has a lower affinity for the β1AR-βarr1 complex than for the β1AR-Gs complex. The structural differences between these complexes of β1AR provide a foundation for the design of small molecules that could bias signalling in the β-adrenoceptors.

G protein-coupled receptors (GPCRs) are involved in many physiological processes and are therefore key drug targets 1. Despite detailed structural information however the effects of lipids on the receptors themselves, or on their downstream coupling to G proteins, are ill defined. Here we use native mass spectrometry to identify endogenous lipids bound to three class A GPCRs. We demonstrate preferential binding of phosphatidylinositol 4,5 bisphosphate (PIP2) over related lipids and confirm hotspots for PIP2 binding on the intracellular face of the receptors. Endogenous lipids were also observed bound directly to the entire adenosine A2A receptor (A2AR) trimeric Gαsβγ protein complex in the gas phase. Recruiting engineered Gα subunits (mini-Gs, i, 12) 2 we found that the β1AR: mini-Gαs complex is stabilised by the binding of two PIP2 molecules. By contrast PIP2 did n 42 ot stabilise coupling between β1AR and other Gα subunits (mini- Gαi, 12) or a high affinity nanobody. Other endogenous lipids that bound to receptors showed no effect on coupling, highlighting the specificity of PIP2. Potential of mean force calculations and increased GTP turnover of the activated neurotensin receptor: trimeric Gαiβγ complex in the presence of PIP2 further support the specific effect of PIP2 on coupling. Together our results identify key residues on cognate Gα subunits that mediate simultaneous PIP2 bridging interactions between basic residues on class A receptors, which do not correspond with those on class B GPCRs. By uncovering the effects of lipid modulation of receptors we highlight consequences for understanding function, G protein selectivity and drug targeting of class A GPCRs.

The incidence of adolescent self-harm and suicidal behaviour has increased globally, with many adolescents repeating the behaviour. While studies indicate that large numbers of adolescents who self-harm do not seek professional help, research focusing on barriers to help seeking from an adolescent perspective is limited. Locally, a rise in reported and unreported rates of self-harm and a number of suspected child suicides prompted the commissioning of a research project to ascertain young people’s experiences of help and support for self-harm and how their future needs could be best met. Qualitative research, adopting an interpretive phenomenological analysis, was used to elicit narratives of adolescents engaging in self-harm. Data were collected via 1:1 interviews with seven participants and analysed in two stages: an analysis of each individual narrative, and thematic analysis across the group. Three themes were identified: (i) cutting out the stress; (ii) stepping onto the path of help; and (iii) cutting to the chase. In conclusion, mental health nurses have a vital role in providing knowledge and support to those likely to have initial contact with this vulnerable group and to the wider population, ensuring we more effectively address the increasing use of this risky behaviour among young people.

This scoping and mapping report is one of three outputs from a project: Explicating the role of partnerships in\ud changing the health and well-being of local communities, one of a number of projects in a larger Higher Education Funding Council Strategic Development Fund project ( HEFCE )\ud entitled: Urban Regeneration: Making a Difference. This was a collaborative venture between Manchester Metropolitan University, Northumbria University, University of Salford and\ud University of Central Lancashire. Bradford University was an affiliated partner.

This literature review is one of three outputs from a project: Explicating the role of partnerships in changing\ud the health and well-being of local communities, one of a number of projects in a larger Higher Education Funding Council Strategic Development Fund project (HEFCE) entitled: Urban Regeneration: Making a Difference. This was a collaborative venture between Manchester Metropolitan University, Northumbria University, University of Salford and University of Central Lancashire. Bradford University was an affiliated partner.