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The archetypal foraging behaviour of tropical seabirds is generally accepted to differ from that of their temperate and polar breeding counterparts, with the former exhibiting less predictable foraging behaviour associated with the less predictable prey of the tropical marine environment. Similarly, temperate and polar species have predictable, annual breeding seasons, enabling them to profit during periods of the year when prey availability is highest, while tropical seabird species exhibit considerable variability in their breeding strategies. Until now, the reasons for such variation in breeding strategies between tropical seabirds are yet to be investigated. We hypothesise that while some tropical species breed asynchronously in response to unpredictable fluctuations in prey availability, others adopt a seasonal breeding strategy for the same reasons that temperate and polar species do. Consequently, the predictability of seabird foraging behaviour in the tropics may be related to breeding strategy, with populations that breed seasonally exhibiting more predictable foraging behaviour than those that breed aseasonally. To test these predictions, we used GPS tracking to examine the foraging behaviour of two closely related tropical seabird species that colonise the same island yet exhibit markedly different breeding strategies: the asynchronously breeding brown booby Sula leucogaster and the seasonal breeding masked booby Sula dactylatra. We obtained tracks for 251 birds over five years. We found that brown boobies forage less predictably than masked boobies, indicated by larger core foraging areas, lower levels of foraging area overlap between individuals and exhibit more variability between breeding periods. Our results challenge the view that the foraging behaviour of tropical seabirds is always less predictable than that of seabirds breeding in temperate and polar regions and highlight the considerable variability in the breeding and foraging strategies adopted by tropical seabirds which demand further exploration. [ABSTRACT FROM AUTHOR]

There is a need for management strategies to control dominant perennial weeds and restore seminatural communities. We compared the effects of five weed control treatments on dense Pteridium aquilinum relative to an untreated experimental control over an 8-year period with the aim of restoring acid grassland. The weed control treatments tested were as follows: cutting and bruising, both twice and thrice annually, and herbicide treatment (asulam in year 1 followed by annual spot retreatment of all emergent fronds). Pteridium aquilinum performance and plant species composition were monitored. Data were analysed using Bayesian mixed-effect models and multivariate techniques. Cutting twice and thrice yearly and the asulam treatment all reduced frond density to zero; both bruising treatments were ineffective. The plant communities in the cut and asulam-treated plots showed differences from the untreated and bruised plots; the asulam-treated plots contained more ruderal species and the cut plots were more typical of acid grassland. Acid grassland recovery was fastest in the asulam-treated plots, but the cut plots caught up after approximately 5 years. There were two important conclusions. First, an intractable weed like P. aquilinum can be eradicated and a vegetation more suited for grazing can be achieved by the continuous application of some treatments over many years. Here, success was achieved by cutting twice/thrice annually, or by a single asulam application followed by annual spot spraying of all emergent fronds for 8 years. Second, bruising, a treatment favoured by some conservation organisations, did not work and cannot be recommended. The use of long-term, continuously applied treatments might be considered for all perennial weeds with large underground root/rhizome systems. [ABSTRACT FROM AUTHOR]

The free fatty acid receptors (FFA) 1 (previously designated GPR40) and FFA4 (previously GPR120) are two GPCRs activated by saturated and unsaturated longer-chain free fatty acids. With expression patterns and functions anticipated to directly or indirectly promote insulin secretion, provide homeostatic control of blood glucose and improve tissue insulin sensitivity, both receptors are being studied as potential therapeutic targets for the control of type 2 diabetes. Furthermore, genetic and systems biology studies in both humans and mouse models link FFA4 receptors to diabetes and obesity. Although activated by the same group of free fatty acids, FFA1 and FFA4 receptors are not closely related and, while the basis of recognition of fatty acids by FFA1 receptors is similar to that of the short-chain fatty acid receptors FFA2 and FFA3, the amino acid residues involved in endogenous ligand recognition by FFA4 receptors are more akin to those of the sphingosine 1 phosphate receptor S1P1 . Screening and subsequent medicinal chemistry programmes have developed a number of FFA1 receptor selective agonists that are effective in promoting insulin secretion in a glucose concentration-dependent manner, and in lowering blood glucose levels. However, the recent termination of Phase III clinical trials employing TAK-875/fasiglifam has caused a setback and raises important questions over the exact nature and mechanistic causes of the problems. Progress in the identification and development of highly FFA4 receptor-selective pharmacological tools has been less rapid and several issues remain to be clarified to fully validate this receptor as a therapeutic target. Despite this, the ongoing development of a range of novel ligands offers great opportunities to further unravel the contributions of these receptors. [ABSTRACT FROM AUTHOR]

The free fatty acid receptors ( FFA) 1 (previously designated GPR40) and FFA4 (previously GPR120) are two GPCRs activated by saturated and unsaturated longer-chain free fatty acids. With expression patterns and functions anticipated to directly or indirectly promote insulin secretion, provide homeostatic control of blood glucose and improve tissue insulin sensitivity, both receptors are being studied as potential therapeutic targets for the control of type 2 diabetes. Furthermore, genetic and systems biology studies in both humans and mouse models link FFA4 receptors to diabetes and obesity. Although activated by the same group of free fatty acids, FFA1 and FFA4 receptors are not closely related and, while the basis of recognition of fatty acids by FFA1 receptors is similar to that of the short-chain fatty acid receptors FFA2 and FFA3, the amino acid residues involved in endogenous ligand recognition by FFA4 receptors are more akin to those of the sphingosine 1 phosphate receptor S1 P1. Screening and subsequent medicinal chemistry programmes have developed a number of FFA1 receptor selective agonists that are effective in promoting insulin secretion in a glucose concentration-dependent manner, and in lowering blood glucose levels. However, the recent termination of Phase III clinical trials employing TAK-875/fasiglifam has caused a setback and raises important questions over the exact nature and mechanistic causes of the problems. Progress in the identification and development of highly FFA4 receptor-selective pharmacological tools has been less rapid and several issues remain to be clarified to fully validate this receptor as a therapeutic target. Despite this, the ongoing development of a range of novel ligands offers great opportunities to further unravel the contributions of these receptors. Linked Articles This article is part of a themed section on 5th BPS Focused Meeting on Cell Signalling. To view the other articles in this section visit [ABSTRACT FROM AUTHOR]

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Background Estimates of psoriatic arthritis (PsA) prevalence among psoriasis patients vary widely (5–40%). The time to development of PsA in patients with plaque psoriasis also remains unclear. Objectives To examine whether length of time since diagnosis of psoriasis affects risk of developing PsA, and to assess differences in quality of life (QoL), work-related issues, comorbidities and healthcare resource utilization (HCRU) for patients with PsA vs. psoriasis. Methods This large cross-sectional observational study was conducted in the UK, Italy, France, Spain and Germany in 2006. Dermatologists who actively treated patients with psoriasis recruited 10 consecutive patients with psoriasis. Presence of PsA, body surface area (BSA) affected with psoriasis and HCRU were recorded; patients completed EUROQoL (EQ5D) and employment disadvantages questionnaires. Results Patients with psoriasis ( n = 1560) included 126 with PsA. Ninety per cent of these patients with PsA were seen by dermatologists who involved a rheumatologist in the care of their patients with PsA. Survival analysis indicated that the incidence of PsA among psoriasis patients remained constant (74 per 1000 person-years), while the prevalence increased with time since diagnosis of psoriasis, reaching 20.5% after 30 years. In addition, those with high BSA currently affected by psoriasis were more likely to have developed PsA ( P < 0.028). PsA patients reported reduced QoL compared with psoriasis patients (EQ5D score: 0.56 vs. 0.82: P < 0.0005), as well as more work problems. PsA patients were more likely to be hospitalized (0.27 ± 0.84 vs. 0.14 ± 0.71 per year; P < 0.0005) and have additional comorbidities than those without PsA. Conclusions The incidence of PsA was constant after initial diagnosis of psoriasis, leading to a higher prevalence of concomitant PsA over time. PsA is associated with decreased QoL and increased work-related problems, HCRU and comorbidities. Dermatologists should screen for PsA in their patients, especially long-standing patients who did not initially present with PsA. [ABSTRACT FROM AUTHOR]

This themed section of BJP includes 11 reviews on the biology of G-protein coupled receptors (GPCRs) and the drug targets that these present, 21 research papers on the pharmacology of a range of GPCRs and Commentaries on four of the papers. Areas reviewed include molecular interactions, particular in respect of hetero-dimerisation between receptors and other membrane-located proteins and other key signalling molecules including cAMP and G12/13 proteins and recently de-orphanised receptors including the Neuromedins U & S and the Free Fatty Acid receptors FFA2 & FFA3. The research papers cover the pharmacology of a range of agents acting at GPCRs, including adrenoceptors, purinoceptors, 5HT, opioid, cannabinoid & PAR-2 receptors. A group of papers is concerned with the interesting and rapidly developing pharmacology of drugs acting at beta(2)-adrenoceptors. The reach of GPCRs is illustrated by the range of physiological systems and therapeutic applications involved, including pain, cancer, cardiovascular, gastrointestinal, visual and respiratory and central nervous systems. [ABSTRACT FROM AUTHOR]

Mu and delta opioid receptors (MORs and DORs) were co-expressed as fusion proteins between a receptor and a pertussis insensitive mutant Gαi/o protein in human embryonic kidney 293 cells. Signalling efficiency was then monitored following inactivation of endogenous Gαi/o proteins by pertussis toxin. Co-expression resulted in increased delta opioid signalling which was insensitive to the mu specific antagonistd-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2. Under these conditions, mu opioid signalling was also increased and insensitive to the delta specific antagonist Tic-deltorphin. In this latter case, however, no G protein activation was observed in the presence of the delta specific inverse agonist N, N(CH3)2-Dmt-Tic-NH2. When a MOR fused to a non-functional Gα subunit was co-expressed with the DOR-Gα protein fusion, delta opioid signalling was not affected whereas mu opioid signalling was restored. Altogether our results suggest that increased delta opioid signalling is due to enhanced DOR coupling to its tethered Gα subunit. On the other hand, our data indicate that increased mu opioid signalling requires an active conformation of the DOR and also results in activation of the Gα subunit fused the DOR. [ABSTRACT FROM AUTHOR]

G protein-coupled receptors are one of the most actively studied families of proteins. However, despite the ubiquity of protein dimerization and oligomerization as a structural and functional motif in biology, until the last decade they were generally considered as monomeric, non-interacting polypeptides. For the metabotropic glutamate-like group of G protein-coupled receptors, it is now firmly established that they exist and function as dimers or, potentially, even within higher-order structures. Despite some evidence continuing to support the view that rhodopsin-like G protein-coupled receptors are predominantly monomers, many recent studies are consistent with the dimerization/oligomerization of such receptors. Key roles suggested for dimerization of G protein-coupled receptors include control of protein maturation and cell surface delivery and providing the correct framework for interactions with both hetero-trimeric G proteins and arrestins to allow signal generation and its termination. As G protein-coupled receptors are the most targeted group of proteins for the development of therapeutic small molecule medicines, recent indications that hetero-dimerization between co-expressed G protein-coupled receptors may be a common process offers the potential for the development of more selective and tissue restricted medicines. However, many of the key experiments have, so far, been limited to model cell systems. Priorities for the future include the generation of tools and reagents able to identify unequivocally potential G protein-coupled receptor hetero-dimers in native tissues and detailed analyses of the influence of hetero-dimerization on receptor function and pharmacology.British Journal of Pharmacology (2008) 153, S216–S229; doi:10.1038/sj.bjp.0707490; published online 29 October 2007 [ABSTRACT FROM AUTHOR]

The receptors that couple to G proteins (GPCR) and which span the cell membranes seven times (7-TM receptors) were the focus of a symposium in Stockholm 2006. The ensemble of GPCR has now been mapped in several animal species. They remain a major focus of interest in drug development, and their diverse physiological and pathophysiological roles are being clarified, i.a. by genetic targeting. Recent developments hint at novel levels of complexity. First, many, if not all, GPCRs are part of multimeric ensembles, and physiology and pharmacology of a given GPCR may be at least partly guided by the partners it was formed together with. Secondly, at least some GPCRs may be constitutively active. Therefore, drugs that are inverse agonists may prove useful. Furthermore, the level of activity may vary in such a profound way between cells and tissues that this could offer new ways of achieving specificity of drug action. Finally, it is becoming increasingly clear that some of these receptors can signal via novel types of pathways, and hence that ‘GPCRs’ may not always be G-protein-coupled. Thus there are many challenges for the basic scientist and the drug industry. [ABSTRACT FROM AUTHOR]

1 Fusion proteins were constructed between the human 5-HT(1A) receptor and pertussis toxin-resistant forms of both G(i1)alpha and G(o1)alpha mutated at residue(351) from cysteine to either glycine or isoleucine. Each of these was expressed stably in HEK293 cells. 2 Increasing concentrations of GDP inhibited binding of the agonist [(3)H]-8-OH-DPAT but not the antagonist [(3)H]-MPPF to each construct. 3 The IC(50) for GDP was greater for constructs containing isoleucine at residue(351) of the G proteins compared to those with glycine at this position. 4 The G protein antagonist suramin had similar effects to GDP on the binding of [(3)H]-8-OH-DPAT. 5 The proportion of 5-HT(1A) receptor binding sites detected by [(3)H]-MPPF that displayed high affinity for 8-OH-DPAT was significantly greater when the interacting G protein contained isoleucine rather than glycine at residue(351). 6 The 5-HT(1A) receptor displayed similar avidity of interaction with G(i1)alpha and G(o1)alpha. 7 These results indicate that a higher avidity ternary complex is formed between 8-OH-DPAT, the 5-HT(1A) receptor and G proteins when isoleucine rather than glycine is located at residue(351) of the interacting G protein. [ABSTRACT FROM AUTHOR]

Recombinant RGS1, RGS16 and RGS–GAIP, but not RGS2, were able to substantially further stimulate the maximal GTPase activity of G[sub o1]α promoted by agonists at the α[sub 2A]-adrenoreceptor in a concentration-dependent manner. Kinetic analysis of the regulation of an α[sub 2A]-adrenoreceptor–G[sub o1]α fusion protein by all three RGS proteins revealed that they had similar affinities for the receptor–G protein fusion. However, their maximal effects on GTP hydrolysis varied over threefold with RGS16 > RGS1 > RGS–GAIP. Both RGS1 and RGS16 reduced the potency of the α[sub 2A]-adrenoreceptor agonist adrenaline by some 10-fold. A lower potency shift was observed for the partial agonist UK14304 and the effect was absent for the weak partial agonist oxymetazoline. Each of these RGS proteins altered the intrinsic activity of both UK14304 and oxymetazoline relative to adrenaline. Such results require the RGS interaction with G[sub o1]α to alter the conformation of the α[sub 2A]-adrenoreceptor and are thus consistent with models invoking direct interactions between RGS proteins and receptors. These studies demonstrate that RGS1, RGS16 and RGS–GAIP show a high degree of selectivity to regulate α[sub 2A]-adrenoreceptor-activated G[sub o1]α rather than G[sub i1]α, G[sub i2]α or G[sub i3]α and different capacities to inactivate this G protein. [ABSTRACT FROM AUTHOR]

To assess the relative capacity of the human δ opioid receptor to activate closely related G proteins, fusion proteins were constructed in which the α-subunits of either G[sub i1] or G[sub o1], containing point mutations to render them insensitive to the actions of pertussis toxin, were linked in-frame with the C-terminus of the receptor. Following transient and stable expression in HEK 293 cells, both constructs bound the antagonist [[sup 3]H]naltrindole with high affinity. d-ala[sup 2],d-leu[sup 5] Enkephalin effectively inhibited forskolin-stimulated adenylyl cyclase activity in intact cells in a concentration-dependent, but pertussis toxin-insensitive, manner. The high-affinity GTPase activity of both constructs was also stimulated by d-ala[sup 2],d-leu[sup 5] enkephalin with similar potency. However, enzyme kinetic analysis of agonist stimulation of GTPase activity demonstrated that the GTP turnover number produced in response to d-ala[sup 2],d-leu[sup 5] enkephalin was more than three times greater for G[sub i1]α than for G[sub o1]α. As the effect of agonist in both cases was to increase V[sub max] without increasing the observed K[sub m] for GTP, this is consistent with receptor promoting greater guanine nucleotide exchange, and thus activation, of G[sub i1]α compared with G[sub o1]α. An equivalent fusion protein between the human µ opioid receptor-1 and G[sub i1]α produced a similar d-ala[sup 2],d-leu[sup 5] enkephalin-induced GTP turnover number as the δ opioid receptor-G[sub i1]α fusion construct, consistent with agonist occupation of these two opioid receptor subtypes being equally efficiently coupled to activation of G[sub i1]α. [ABSTRACT FROM AUTHOR]

The molecular mechanisms underlying B- and T-cell development are, as yet, poorly understood. However, as G proteins regulate a diverse range of biological responses including growth, proliferation and differentiation, we have investigated differential expression of G proteins during B- and T-cell development with the aim of identifying key signals involved in lymphocyte maturation. Differential expression of β½ and α-subunits of the Gs-, i' and q-families was found throughout lymphoid development. Most strikingly, Gα11 and Gα11 were very weakly, or not expressed in pre-, immature and mature B cells, thymocytes or mature T cells, but strongly induced in mature B-lymphoblastoid cell lines, some of which have been used as models of germinal centre B cells, suggesting that expression of these G proteins may correlate with the later stages of Ball development. In contrast, Gα16 expression was highest in T cells and pre-B cells and progressively declined with B-cell maturation. These findings suggest that G proteins, and the signals they regulate, such as ion channels and/or adenylate cyclase (Gα2/1) and phospholipase C (Gβγ and Gα11/16) are differentially regulated in lymphoid cells in a maturation- and lineage-dependent manner. [ABSTRACT FROM AUTHOR]

Alopecia area (AA) is a common autoimmune disorder, characterized by hair loss. Although its impact on quality of life is fairly well understood, studies on the economic impact of AA are limited. The aim of this study was to quantify the personal and nationwide economic burden of AA in Japan. Data were drawn from the Adelphi AA Disease Specific Programme (DSP)™, a real-world, cross-sectional survey with retrospective data collection, of Japanese physicians and patients with AA. The study was conducted in 2021, before the approval of Janus kinase inhibitors for AA. Physicians and their consulting AA patients completed questionnaires regarding disease severity, treatment, and AA-related costs. The Work Productivity and Activity Impairment questionnaire was used to evaluate the impact of AA on patients' work and activity. Nationwide estimates of cost and productivity loss were extrapolated from collected patient data. A total of 50 physicians provided data on 235 patients; 58.7% were female, mean ± SD age was 41.1 ± 11.8 years, and mean physician-estimated scalp hair loss was 40.4% ± 30.2%. Prescription medication use was high (92.3% of patients), but the use of over-the-counter medication was low, at 8.7%. Mean cost to patients for medication was ¥ 4263 (US$ 32.42) per month. Productivity while at work (presenteeism) was significantly impaired (23.9% ± 25.7%), but absenteeism was low (0.9% ± 2.8%). The total nationwide cost of AA was estimated at 112.7 billion yen (US$ 857 million), of which 88.1 billion yen (78.2%) was due to productivity loss. Over 2 million days per year of activity time were estimated to be lost due to AA. Thus, despite not being a physically limiting disease, AA has a significant impact in terms of cost and time, both on a personal and national level. These data highlight the need for more targeted interventions to reduce the effects of AA on the Japanese economy., (© 2023 Pfizer Japan Inc, Adelphi Real World and The Authors. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Vascular endothelial cells derived from human pluripotent stem cells have substantial potential for the development of novel vascular therapeutics and cell-based therapies for the repair of ischemic damage. To gain maximum benefit from this source of cells, a complete understanding of the changes in gene expression and how they are regulated is required. miRNAs have been demonstrated to play a critical role in controlling stem cell pluripotency and differentiation and are important for mature endothelial cell function. Specific miRNAs that determine stem cell fate have been identified for a number of different cell lineages; however, in the case of differentiation and specification of vascular endothelial cells, this is yet to be fully elucidated., (© 2012 John Wiley & Sons Ltd.)

Although many G-protein-coupled neurotransmitter receptors are potentially capable of modulating both voltage-dependent Ca(2+) channels (I(Ca)) and G-protein-gated K(+) channels (I(GIRK)), there is a substantial degree of selectivity in the coupling to one or other of these channels in neurons. Thus, in rat superior cervical ganglion (SCG) neurons, M(2) muscarinic acetylcholine receptors (mAChRs) selectively activate I(GIRK) whereas M(4) mAChRs selectively inhibit I(Ca). One source of selectivity might be that the two receptors couple preferentially to different G-proteins. Using antisense depletion methods, we found that M(2) mAChR-induced activation of I(GIRK) is mediated by G(i) whereas M(4) mAChR-induced inhibition of I(Ca) is mediated by G(oA). Experiments with the beta gamma-sequestering peptides alpha-transducin and beta ARK1(C-ter) indicate that, although both effects are mediated by G-protein beta gamma subunits, the endogenous subunits involved in I(GIRK) inhibition differ from those involved in I(Ca) inhibition. However, this pathway divergence does not result from any fundamental selectivity in receptor-G-protein-channel coupling because both I(GIRK) and I(Ca) modulation can be rescued by heterologously expressed G(i) or G(o) proteins after the endogenously coupled alpha-subunits have been inactivated with Pertussis toxin (PTX). We suggest instead that the divergence in the pathways activated by the endogenous mAChRs results from a differential topographical arrangement of receptor, G-protein and ion channel.

One postsynaptic action of the transmitter acetylcholine in sympathetic ganglia is to inhibit somatic N-type Ca2+ currents: this reduces Ca2+-activated K+ currents and facilitates high-frequency spiking. Previous experiments on rat superior cervical ganglion neurons have revealed two distinct pathways for this inhibitory action: a rapid, voltage-dependent inhibition through activation of M4 muscarinic acetylcholine receptors (mAChRs), and a slower, voltage-independent inhibition via M1 mAChRs [Hille (1994) Trends in Neurosci., 17, 531-536]. We have analysed the mechanistic basis for this divergence at the level of the individual G-proteins and their alpha and betagamma subunits, using a combination of site-directed antibody injection, plasmid-driven antisense RNA expression, overexpression of selected constitutively active subunits, and antagonism of endogenously liberated betagamma subunits by over-expression of Dy-binding P-adrenergic receptor kinase 1 (PARK1) peptide. The results indicate that: (i) M4 mAChR-induced inhibition is mediated by GoA; (ii) a and Py subunits released from the activated GoA heterotrimer produce separate voltage-insensitive and voltage-sensitive components of inhibition, respectively; and (iii) voltage-insensitive M1 mAChR-induced inhibition is likely to be mediated by the alpha subunit of Gq. Hence, Ca2+ current inhibition results from the concerted, but independent actions of three different G-protein subunits.