Signal transduction at GPCRs: Allosteric activation of the ERK MAPK by ß-arrestin.

ß-arrestins are multivalent adaptor proteins that bind active phosphorylated G protein-coupled receptors (GPCRs) to inhibit G protein signaling, mediate receptor internalization, and initiate alternative signaling events. ß-arrestins link agonist-stimulated GPCRs to downstream signaling partners, such as the c-Raf-MEK1-ERK1/2 cascade leading to ERK1/2 activation. ß-arrestins have been thought to transduce signals solely via passive scaffolding by facilitating the assembly of multiprotein signaling complexes. Recently, however, ß-arrestin 1 and 2 were shown to activate two downstream signaling effectors, c-Src and c-Raf, allosterically. Over the last two decades, ERK1/2 have been the most intensely studied signaling proteins scaffolded by ß-arrestins. Here, we demonstrate that ß-arrestins play an active role in allosterically modulating ERK kinase activity in vitro and within intact cells. Specifically, we show that ß-arrestins and their GPCR-mediated active states allosterically enhance ERK2 autophosphorylation and phosphorylation of a downstream ERK2 substrate, and we elucidate the mechanism by which ß-arrestins do so. Furthermore, we find that allosteric stimulation of dually phosphorylated ERK2 by active-state ß-arrestin 2 is more robust than by active-state ß-arrestin 1, highlighting differential capacities of ß-arrestin isoforms to regulate effector signaling pathways downstream of GPCRs. In summary, our study provides strong evidence for a new paradigm in which ß-arrestins function as active "catalytic" scaffolds to allosterically unlock the enzymatic activity of signaling components downstream of GPCR activation.

Ways of coping and the health of relatives facing drug and alcohol problems in Mexico and England.

AIMS: To compare two contrasting socio-cultural groups in terms of parameters relating to the stress - coping - health model of alcohol, drugs and the family, and to test hypotheses derived from the model in each of the two groups separately. DESIGN: Cross-sectional, comparative and correlational, using standard questionnaire data, supplemented by qualitative interview data to illuminate the findings. PARTICIPANTS: One hundred close relatives, mainly partners or parents, from separate families in Mexico City, and 100 from South West England. Data sources. Coping Questionnaire (CQ), Family Environment Scale (FES), Symptom Rating Test (SRT), Semi-structured interview. FINDINGS: Mean symptom scores were high in both groups, and not significantly different. The hypothesis that relatives in Mexico City, a more collectivist culture, would show more tolerant - inactive coping was not supported, but there was support for the prediction that relatives in South West England would show more withdrawal coping. This result may be as much due to differences in poverty and social conditions as to differences in individualism - collectivism. As predicted by the stress - coping - health model, tolerant - inactive coping was correlated with symptoms, in both groups, after controlling for family conflict, but there was only limited support for a moderating role of coping. Wives of men with alcohol problems in Mexico City, and wives of men with other drug problems in South West England, reported particularly high levels of both engaged and tolerant - inactive coping. CONCLUSIONS: Tolerant - inactive coping may be bad for relatives' health: causality may be inferred but is not yet proved. Certain groups are more at risk of coping in this way. Qualitative data help understand the nature of tolerant - inactive coping and why it occurs despite the view of relatives themselves that it is counter-productive.

Tolerate, engage or withdraw: a study of the structure of families coping with alcohol and drug problems in south west England and Mexico City.

AIMS: To explore the structure underlying individual differences in the ways family members cope with drinking or drug problems. DESIGN: Cross-sectional interview and questionnaire study of a series of family members in two contrasting socio-cultural groups. SETTING: Mexico City and South West England. PARTICIPANTS: Two hundred and seven family members from separate families, three-quarters women, one-quarter men, mostly partners or parents. DATA: Long semi-structured interviews; the Coping Questionnaire (CQ). FINDINGS: Factor and subscale analyses of the CQ data and textual analysis of the interview reports were used to test the hypothesis that the underlying structure to coping could be described in terms of eight or nine coherent and distinct ways of coping. Neither form of analysis gave strong support to this hypothesis. CONCLUSIONS: It is concluded that the structure of coping can best be described in terms of three broad coping positions: tolerating, engaging and withdrawing. These conclusions challenge some previous assumptions about functional and dysfunctional ways of coping with excessive appetitive behaviour in the family.

'Role' as a moral concept in health care.

In this article, it is argued that an appropriate starting point for an analysis of ethical issues in health care is the consideration of the role obligation of health care professionals. These obligations have customary, legal, and moral elements. By appreciating the different kinds of health care roles and their purposes, one can begin to understand some of the role conflicts which arise in the health care community. Moreover, one can see that some criticisms of health care professionals are mistaken. Nonetheless, there are internal conflicts with the roles of persons engaged in health care and historically some role obligations have violated fundamental universal norms. Whereas the latter inadequacy of health care role obligations can be eliminated, the former will, to at least some extent, always be with us. In short, it may be argued that some of the so-called "moral dilemmas"in health care can be resolved by taking the perspective of role morality. As will be shown, this does not suggest that there are no limitations of role morality.

KIE: Role analysis is proposed as an efficacious starting point for a discussion of ethical issues in health care. The role obligations of health care professionals form the framework within which ethical decisions are made. These obligations are comprised of legal, customary, and moral elements that are complicated by the multiple roles individuals play. Internal conflicts inevitably arise, and some specific obligations of health care professionals have historically violated universal moral norms.