Defining and unpacking the core concepts of pharmacology: A global initiative.

BACKGROUND AND PURPOSE: Development of core concepts in disciplines such as biochemistry, microbiology and physiology have transformed teaching. They provide the foundation for the development of teaching resources for global educators, as well as valid and reliable approaches to assessment. An international research consensus recently identified 25 core concepts of pharmacology. The current study aimed to define and unpack these concepts. EXPERIMENTAL APPROACH: A two-phase, iterative approach, involving 60 international pharmacology education experts, was used. The first phase involved drafting definitions for core concepts and identifying key sub-concepts via a series of online meetings and asynchronous work. These were refined in the second phase, through a 2-day hybrid workshop followed by a further series of online meetings and asynchronous work. KEY RESULTS: The project produced consensus definitions for a final list of 24 core concepts and 103 sub-concepts of pharmacology. The iterative, discursive methodology resulted in modification of concepts from the original study, including change of 'drug-receptor interaction' to 'drug-target interaction' and the change of the core concept 'agonists and antagonists' to sub-concepts of drug-target interaction. CONCLUSIONS AND IMPLICATIONS: Definitions and sub-concepts of 24 core concepts provide an evidence-based foundation for pharmacology curricula development and evaluation. The next steps for this project include the development of a concept inventory to assess acquisition of concepts, as well as the development of case studies and educational resources to support teaching by the global pharmacology community, and student learning of the most critical and fundamental concepts of the discipline.

Developing an international concept-based curriculum for pharmacology education: The promise of core concepts and concept inventories.

Over recent years, studies have shown that science and health profession graduates demonstrate gaps in their fundamental pharmacology knowledge and ability to apply pharmacology concepts in practice. This article reviews the current challenges faced by pharmacology educators, including the exponential growth in discipline knowledge and competition for curricular time. We then argue that pharmacology education should focus on essential concepts that enable students to develop beyond 'know' towards 'know how to'. A concept-based approach will help educators prioritize and benchmark their pharmacology curriculum, facilitate integration of pharmacology with other disciplines in the curriculum, create alignment between universities and improve application of pharmacology knowledge to professional contexts such as safe prescribing practices. To achieve this, core concepts first need to be identified and unpacked, and methods for teaching and assessment using concept inventories developed. The International Society for Basic and Clinical Pharmacology Education Section (IUPHAR-Ed) Core Concepts of Pharmacology (CCP) initiative involves over 300 educators from the global pharmacology community. CCP has identified and defined the core concepts of pharmacology, together with key underpinning sub-concepts. To realize these benefits, pharmacology educators must develop methods to teach and assess core concepts. Work to develop concept inventories is ongoing, including identifying student misconceptions of the core concepts and creating a bank of multiple-choice questions to assess student understanding. Future work aims to develop and validate materials and methods to help educators embed core concepts within curricula. Potential strategies that educators can use to overcome factors that inhibit adoption of core concepts are presented.

Identifying the core concepts of pharmacology education: A global initiative.

BACKGROUND AND PURPOSE: In recent decades, a focus on the most critical and fundamental concepts has proven highly advantageous to students and educators in many science disciplines. Pharmacology, unlike microbiology, biochemistry, or physiology, lacks a consensus list of such core concepts. EXPERIMENTAL APPROACH: We sought to develop a research-based, globally relevant list of core concepts that all students completing a foundational pharmacology course should master. This two-part project consisted of exploratory and refinement phases. The exploratory phase involved empirical data mining of the introductory sections of five key textbooks, in parallel with an online survey of over 200 pharmacology educators from 17 countries across six continents. The refinement phase involved three Delphi rounds involving 24 experts from 15 countries across six continents. KEY RESULTS: The exploratory phase resulted in a consolidated list of 74 candidate core concepts. In the refinement phase, the expert group produced a consensus list of 25 core concepts of pharmacology. CONCLUSION AND IMPLICATIONS: This list will allow pharmacology educators everywhere to focus their efforts on the conceptual knowledge perceived to matter most by experts within the discipline. Next steps for this project include defining and unpacking each core concept and developing resources to help pharmacology educators globally teach and assess these concepts within their educational contexts.

Evidences for Mutant Huntingtin Inducing Musculoskeletal and Brain Growth Impairments via Disturbing Testosterone Biosynthesis in Male Huntington Disease Animals.

Body weight (BW) loss and reduced body mass index (BMI) are the most common peripheral alterations in Huntington disease (HD) and have been found in HD mutation carriers and HD animal models before the manifestation of neurological symptoms. This suggests that, at least in the early disease stage, these changes could be due to abnormal tissue growth rather than tissue atrophy. Moreover, BW and BMI are reported to be more affected in males than females in HD animal models and patients. Here, we confirmed sex-dependent growth alterations in the BACHD rat model for HD and investigated the associated contributing factors. Our results showed growth abnormalities along with decreased plasma testosterone and insulin-like growth factor 1 (IGF-1) levels only in males. Moreover, we demonstrated correlations between growth parameters, IGF-1, and testosterone. Our analyses further revealed an aberrant transcription of testosterone biosynthesis-related genes in the testes of BACHD rats with undisturbed luteinizing hormone (LH)/cAMP/PKA signaling, which plays a key role in regulating the transcription process of some of these genes. In line with the findings in BACHD rats, analyses in the R6/2 mouse model of HD showed similar results. Our findings support the view that mutant huntingtin may induce abnormal growth in males via the dysregulation of gene transcription in the testis, which in turn can affect testosterone biosynthesis.

Inter-ethnic differences in pharmacokinetics-is there more that unites than divides?

Inter-ethnic variability in pharmacokinetics (PK) has been attributed to several factors ranging from genetic to environmental. It is not clear how current teaching in higher education (HE) reflects what published literature suggests on this subject. This study aims to gain insights into current knowledge about inter-ethnic differences in PK based on reports from published literature and current teaching practices in HE. A systematic literature search was conducted on PubMed and Scopus to identify suitable literature to be reviewed. Insights into inter-ethnic differences in PK teaching among educators in HE and industry were determined using a questionnaire. Thirty-one percent of the studies reviewed reported inter-ethnic differences in PK, of these, 37% of authors suggested genetic polymorphism as possible explanation for the inter-ethnic differences observed. Other factors authors proposed included diet and weight differences between ethnicities. Most respondents (80%) who taught inter-ethnic difference in PK attributed inter-ethnic differences to genetic polymorphism. While genetic polymorphism is one source of variability in PK, the teaching of genetic polymorphism is better associated with interindividual variabilities rather than inter-ethnic differences in PK as there are no genes with PK implications specific to any one ethnic group. Nongenetic factors such as diet, weight, and environmental factors, should be highlighted as potential sources of interindividual variation in the PK of drugs.

Mapping protein interactions of sodium channel NaV1.7 using epitope-tagged gene-targeted mice.

The voltage-gated sodium channel NaV1.7 plays a critical role in pain pathways. We generated an epitope-tagged NaV1.7 mouse that showed normal pain behaviours to identify channel-interacting proteins. Analysis of NaV1.7 complexes affinity-purified under native conditions by mass spectrometry revealed 267 proteins associated with Nav1.7 in vivo The sodium channel ß3 (Scn3b), rather than the ß1 subunit, complexes with Nav1.7, and we demonstrate an interaction between collapsing-response mediator protein (Crmp2) and Nav1.7, through which the analgesic drug lacosamide regulates Nav1.7 current density. Novel NaV1.7 protein interactors including membrane-trafficking protein synaptotagmin-2 (Syt2), L-type amino acid transporter 1 (Lat1) and transmembrane P24-trafficking protein 10 (Tmed10) together with Scn3b and Crmp2 were validated by co-immunoprecipitation (Co-IP) from sensory neuron extract. Nav1.7, known to regulate opioid receptor efficacy, interacts with the G protein-regulated inducer of neurite outgrowth (Gprin1), an opioid receptor-binding protein, demonstrating a physical and functional link between Nav1.7 and opioid signalling. Further information on physiological interactions provided with this normal epitope-tagged mouse should provide useful insights into the many functions now associated with the NaV1.7 channel.

Regulation of Nav1.7: A Conserved SCN9A Natural Antisense Transcript Expressed in Dorsal Root Ganglia.

The Nav1.7 voltage-gated sodium channel, encoded by SCN9A, is critical for human pain perception yet the transcriptional and post-transcriptional mechanisms that regulate this gene are still incompletely understood. Here, we describe a novel natural antisense transcript (NAT) for SCN9A that is conserved in humans and mice. The NAT has a similar tissue expression pattern to the sense gene and is alternatively spliced within dorsal root ganglia. The human and mouse NATs exist in cis with the sense gene in a tail-to-tail orientation and both share sequences that are complementary to the terminal exon of SCN9A/Scn9a. Overexpression analyses of the human NAT in human embryonic kidney (HEK293A) and human neuroblastoma (SH-SY5Y) cell lines show that it can function to downregulate Nav1.7 mRNA, protein levels and currents. The NAT may play an important role in regulating human pain thresholds and is a potential candidate gene for individuals with chronic pain disorders that map to the SCN9A locus, such as Inherited Primary Erythromelalgia, Paroxysmal Extreme Pain Disorder and Painful Small Fibre Neuropathy, but who do not contain mutations in the sense gene. Our results strongly suggest the SCN9A NAT as a prime candidate for new therapies based upon augmentation of existing antisense RNAs in the treatment of chronic pain conditions in man.

The population ecology of two tropical trees, Brachychiton diversifolius (Malvaceae) and Bombax ceiba (Bombaceae), harvested by Indigenous woodcarvers in Arnhem Land, Australia.

We describe the population ecology of two tropical deciduous trees, Bombax ceiba leiocarpum A. Robyns and Brachychiton diversifolius R. Br., which are in high demand for Indigenous sculpture production in Arnhem Land, Australia. We monitored tagged populations of both species at two locations for 2 years to examine their reproduction, growth, and survival rates and their response to harvest. Both species have similar life histories: they reproduce during the dry season (June-November) producing a high seed load, seed predation was high, seeds did not survive in the soil past the following wet season to form a seed bank, and germination rates were low and variable for both species. Average annual circumference growth rates were 1.07 cm year(-1) for B. ceiba and 0.98 cm year(-1) for B. diversifolius, with most of the growth occurring during the early wet season. Most (65-88 %) of the harvested B. ceiba and B. diversifolius stems coppiced. Coppice and stem size class were the main factors influencing tree growth rates with coppice stems growing up to six times faster than similar sized non-coppice stems. The survival of B. ceiba and B. diversifolius stems was size class dependent and affected by local site factors (e.g. fire and other disturbances) so that the smaller size classes had a low probability of survival. Given the resprouting potential of both species, their wild harvest is likely to have only minimal local impact on wild populations. However, further population modelling is required to determine whether the small and disjunct B. ceiba populations can sustain harvesting at current levels.

Assessment of receptor internalization and recycling.

Internalization of G-protein-coupled receptors (GPCRs) occurs in response to agonist activation of the receptors and causes a redistribution of receptors away from the plasma membrane toward endosomes. Internalization of lower-affinity small molecule GPCRs such as muscarinic acetylcholine and adrenergic receptors has been measured using hydrophilic antagonist radioligands that are membrane impermeant. In contrast, internalization of peptide hormone receptors is assessed by measuring the internalization of a radiolabeled- or fluorescently labeled peptide hormone. More recently, the use of epitope-tagged receptors has allowed the measurement of changes in receptor subcellular distribution by the use of immunoassay and immunofluorescence confocal microscopy. This chapter describes each of these approaches to the measurement of receptor internalization and describes the advantages and disadvantages of each method.

Agonist-induced desensitization and endocytosis of heterodimeric GABAB receptors in CHO-K1 cells.

gamma-Aminobutyric acid B (GABA(B)) receptor is the first discovered G protein-coupled receptor that requires two subunits, GB1 and GB2, to form a functional receptor. Whereas the molecular and functional characteristics of GABA(B) receptors have been recently extensively studied, the mechanisms underlying receptor desensitization and endocytosis are still poorly understood. We have investigated the effect of continuous agonist exposure on the human GABA(B) receptor functional response and redistribution when expressed in Chinese hamster ovary (CHO-K1) cells. The wild-type GABA(B) receptor-mediated inhibition of the adenylate cyclase activity appeared desensitized after 2 h in the presence of GABA (100 microM). Fusion proteins were generated by attachment of cyan fluorescent protein (CFP) and yellow fluorescent protein (YFP) to GB1 and GB2, respectively, and confocal microscopy experiments in intact living cells semi-stably expressing the constructs were performed. Incubation of co-expressing CFP-GB1 and YFP-GB2 cells in the presence of GABA (100 microM) for 2 h induced a profound receptor internalization, and CFP-GB1 and YFP-GB2 appeared co-localized in the endosome (labelled with Cy3-transferrin). The internalization was blocked by a selective GABA(B) receptor antagonist. These results represent the first clear visualization of agonist-induced internalization of the unique heterodimeric GABA(B) receptor.