Chaplaincy and spiritual care in Australian ambulance services: an exploratory cross-sectional study.

Ambulance staff wellbeing programs aim to support the bio-psycho-social and sometimes spiritual needs of paramedics. While evidence demonstrates strong connections between spirituality and/or religion to wellbeing outcomes, little is known about spiritual care in ambulance services or its impact. The aim of this study was to investigate paramedics' perspectives on the role and value of Australian ambulance chaplains. A cross-sectional online study of registered paramedics in Australia was conducted between November and December 2022. Analysis of the 150 responses identified that paramedics viewed the chaplain's role as one built on professional caring relationships that provided proactive and reactive care in paramedic workplaces. Chaplains were perceived to promote wellbeing by incorporating emotional, psychological, social and spiritual care, and assisting paramedics to access additional support. Perceived religiousness of chaplains and organisational factors were barriers to paramedics accessing chaplains, while pre-existing relationships and shared experiences positively influenced paramedics decision to seek chaplain support.

Military Perspectives on the Provision of Spiritual Care in the Australian Defence Force: A Cross-Sectional Study.

A module to explore perspectives on chaplaincy services was included in an online enterprise survey randomly distributed to members of the Australian Defence Force (ADF) during 2021. Up to eight questions were answered by 2783 active military personnel relating to their perception of chaplain activities and the impact of chaplaincy services. Of those military participants answering the question on religious status (n = 1116), a total of 71.6% (n = 799) of respondents identified as non-religious while 28.4% (n = 317) identified as holding a religious affiliation. Approximately 44.2% (n = 1230) of participants had sought support from a chaplain, of which 85.3% (n = 1049) found chaplaincy care to be satisfactory or very satisfactory. While the data suggest there is a lack of clarity around the multiple roles undertaken by chaplaincy, nevertheless respondents were just as likely to prefer chaplains for personal support (24.0%), as they were to seek help from non-chaplaincy personnel such as a non-ADF counsellor (23.2%), their workplace supervisor (23.1%) or a psychologist (21.8%). This evidence affirms that the spiritual care provided by military chaplaincy remains one of several preferred choices and thus a valued part of the holistic care provided by the ADF to support the health and wellbeing of its members.

Patient's views of empathic and compassionate healthcare interactions: A scoping review.

BACKGROUND: Compassion and empathy are integral to safe and effective patient care. However, to date, most studies have focused on exploring, defining, measuring and analysing empathy and compassion from the perspective of researchers or clinicians. There has been limited attention to the perspectives of patients. OBJECTIVE: The objective of this scoping review was to map the literature to identify patients' views of healthcare provider behaviours that exemplify empathic and compassionate interactions. METHOD: This review used the Joanna Briggs Institute scoping review methodology. A comprehensive search of eight electronic databases was conducted with English language studies published in the last 10 years considered for inclusion. RESULTS: Database searching resulted in 459 records for initial screening. After de-duplication and conducting a title and abstract review, 32 full-text articles were screened for eligibility. A total of 14 studies met the inclusion criteria and were critically reviewed using the Mixed Methods Appraisal Tool. The included papers profiled studies that had been conducted in clinical settings across seven countries. The healthcare encounters described in the papers were with a range of healthcare providers. Two overarching and interconnected categories of behaviours were identified as indicative of empathic/compassionate encounters: (1) communication skills such as listening, touch, body language, eye contact and positive demeanour; and (2) helping behaviours demonstrated by small acts of kindness that go beyond routine healthcare. CONCLUSION: Given the breadth of studies describing the positive impact of empathy/compassion on people's physical and psychosocial wellbeing, the results from this review are valuable and shed new light on patients' views and experiences. The results provide a deeper understanding of healthcare provider behaviours that exemplify empathic and compassionate healthcare interactions and can be used to inform the education and training of healthcare providers from all disciplines.

Pharmacological hallmarks of allostery at the M4 muscarinic receptor elucidated through structure and dynamics.

Allosteric modulation of G protein-coupled receptors (GPCRs) is a major paradigm in drug discovery. Despite decades of research, a molecular-level understanding of the general principles that govern the myriad pharmacological effects exerted by GPCR allosteric modulators remains limited. The M4 muscarinic acetylcholine receptor (M4 mAChR) is a validated and clinically relevant allosteric drug target for several major psychiatric and cognitive disorders. In this study, we rigorously quantified the affinity, efficacy, and magnitude of modulation of two different positive allosteric modulators, LY2033298 (LY298) and VU0467154 (VU154), combined with the endogenous agonist acetylcholine (ACh) or the high-affinity agonist iperoxo (Ipx), at the human M4 mAChR. By determining the cryo-electron microscopy structures of the M4 mAChR, bound to a cognate Gi1 protein and in complex with ACh, Ipx, LY298-Ipx, and VU154-Ipx, and applying molecular dynamics simulations, we determine key molecular mechanisms underlying allosteric pharmacology. In addition to delineating the contribution of spatially distinct binding sites on observed pharmacology, our findings also revealed a vital role for orthosteric and allosteric ligand-receptor-transducer complex stability, mediated by conformational dynamics between these sites, in the ultimate determination of affinity, efficacy, cooperativity, probe dependence, and species variability. There results provide a holistic framework for further GPCR mechanistic studies and can aid in the discovery and design of future allosteric drugs.

Calcium-Sensing Receptor Negative Allosteric Modulators Oppose Contraction of Mouse Airways.

Asthma is a heterogeneous chronic airway disease with an unmet need for improved therapeutics in uncontrolled severe disease. The calcium-sensing receptor (CaSR) is a G protein-coupled receptor upregulated in asthma. The CaSR agonist, spermine, is also increased in asthmatic airways and contributes to bronchoconstriction. CaSR negative allosteric modulators (NAMs) oppose chronic airway inflammation, remodeling, and hyperresponsiveness in murine and guinea pig asthma models, but whether CaSR NAMs are effective acute bronchodilators compared with standard of care has not yet been established. Furthermore, the ability of different classes of NAMs to inhibit spermine-induced CaSR signaling or methacholine (MCh)-induced airway contraction has not been quantified. Here, we show CaSR NAMs differentially inhibit spermine-induced intracellular calcium mobilization and inositol monophosphate accumulation in HEK293 cells stably expressing the CaSR. NAMs reverse MCh-mediated airway contraction in mouse precision-cut lung slices with similar maximal relaxation compared with the standard treatment, salbutamol. Of note, the bronchodilator effects of CaSR NAMs are maintained under conditions of ß2-adrenergic receptor desensitization when salbutamol efficacy is abolished. Furthermore, overnight treatment with some, but not all, CaSR NAMs prevents MCh-mediated bronchoconstriction. These findings further support the CaSR as a putative drug target and NAMs as alternative or adjunct bronchodilators in asthma.

The Role and Value of Chaplains in an Australian Ambulance Service: A Comparative Study of Chaplain and Paramedic Perspectives.

Chaplains are embedded in several ambulance services across Australia, however as Australia's religiosity is currently in decline and questions are being asked about retaining chaplains, little is actually known about their role and value within Ambulance services. The aim of this paper is to present the key findings from interviews with chaplains about their role and value of being ambulance chaplains. These findings are then compared with those of paramedics derived from an earlier phase of this study. Thirteen chaplains participated in semi-structured interviews, and data were analysed using framework analysis. The results indicated that ambulance chaplains provided paramedic-centred emotional and spiritual care through proactively and reactively supporting paramedics in their work. Chaplains saw value in their relational approach which facilitated trust and access, did not seek to 'fix' or diagnose but instead offered physical and emotional presence, and promoted supportive conversations. Chaplains and paramedics valued operationally trained and equipped ambulance chaplains who provided a relational, around the clock, 'frontline' staff support presence in paramedic workplaces, regardless of the paramedic's personal religious/spiritual beliefs.

Cell Surface Calcium-Sensing Receptor Heterodimers: Mutant Gene Dosage Affects Ca2+ Sensing but Not G Protein Interaction.

The calcium-sensing receptor is a homodimeric class C G protein-coupled receptor (GPCR) that senses extracellular Ca2+ (Ca2+ o ) via a dimeric extracellular Venus flytrap (VFT) unit that activates G protein-dependent signaling via twin Cysteine-rich domains linked to transmembrane heptahelical (HH) bundles. It plays a key role in the regulation of human calcium and thus mineral metabolism. However, the nature of interactions between VFT units and HH bundles, and the impacts of heterozygous or homozygous inactivating mutations, which have implications for disorders of calcium metabolism are not yet clearly defined. Herein we generated CaSR-GABAB1 and CaSR-GABAB2 chimeras subject to GABAB -dependent endoplasmic reticulum sorting to traffic mutant heterodimers to the cell surface. Transfected HEK-293 cells were assessed for Ca2+ o -stimulated Ca2+ i mobilization using mutations in either the VFT domains and/or HH bundle intraloop-2 or intraloop-3. When the same mutation was present in both VFT domains of receptor dimers, analogous to homozygous neonatal severe hyperparathyroidism (NSHPT), receptor function was markedly impaired. Mutant heterodimers containing one wild-type (WT) and one mutant VFT domain, however, corresponding to heterozygous familial hypocalciuric hypercalcemia type-1 (FHH-1), supported maximal signaling with reduced Ca2+ o potency. Thus two WT VFT domains were required for normal Ca2+ o potency and there was a pronounced gene-dosage effect. In contrast, a single WT HH bundle was insufficient for maximal signaling and there was no functional difference between heterodimers in which the mutation was present in one or both intraloops; ie, no gene-dosage effect. Finally, we observed that the Ca2+ o -stimulated CaSR operated exclusively via signaling in-trans and not via combined in-trans and in-cis signaling. We consider how receptor asymmetry may support the underlying mechanisms. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Personalised medicines for familial hypercalcemia and hyperparathyroidism.

Loss-of-function calcium-sensing receptor (CASR) mutations cause mineral metabolism disorders, familial hypocalciuric hypercalcemia, or neonatal severe hyperparathyroidism and increase the risk of femoral fracture, chronic kidney disease, coronary heart disease, and other diseases. In severe cases, CaSR mutations are lethal. Off-label use of the CaSR-positive allosteric modulator (PAM), cinacalcet, corrects hypercalcemia in some patients with CaSR mutations. However, other patients remain unresponsive to cinacalcet, attesting to the need for novel treatments. Here, we compared the effects of cinacalcet to two other clinically approved synthetic CaSR activators, evocalcet and etelcalcetide, as well as a novel PAM, 1-(2,4-dimethylphenyl)-1-(4,5-dimethylthiazol-2-yl)ethan-1-ol (MIPS-VD-836-108) on clinically relevant CaSR mutations. We assessed the compounds in CaSR-expressing HEK293 cells for correction of mutation-induced impairments in intracellular calcium (Ca2+i) mobilization and cell surface expression. While cinacalcet, MIPS-VD-836-108 and evocalcet rescued the signaling of cell surface-expressed mutants, albeit to varying degrees, etelcalcetide was ineffective. Cinacalcet and evocalcet, but not MIPS-VD-836-108 or etelcalcetide, restored the expression of a R680H mutant. However, no compound rescued expression of I81K and C582R mutants or a receptor missing 77 amino acids in the extracellular domain mimicking deletion of CASRexon 5, which impairs CaSR function. These data suggest specific compounds may be clinically effective in some patients with CaSR mutations, but other patients will remain refractory to treatment with currently available CaSR-targeting activators, highlighting the need for new generation drugs to rescue both the signaling and expression of mutant CaSRs.

The utilisation of vaccines in humanitarian crises, 2015-2019: A review of practice.

BACKGROUND: The risk factors that emerge with the onset and protraction of humanitarian crises leave populations at a heightened risk of excess morbidity and mortality from vaccine-preventable diseases (VPDs). There is currently little clarity on which vaccines are being used in crises throughout the world, and whether vaccination decisions correspond to local disease threats. This review aimed to collect and analyse such information. METHODS: We reviewed vaccination services from January 2015 to June 2019 across all 25 humanitarian responses that had an activated coordination mechanism during this period. A range of online sources and informants within the humanitarian sector were consulted to compile data on which vaccines were provided in each crisis, and the modality and timing of vaccine provision. The package of vaccination services since the start of each crisis was then compared with local disease burden (baseline + excess due to crisis-emergent risk factors). RESULTS: The range of vaccines used in humanitarian crises appears limited. When offered, vaccines were primarily delivered through the pre-existing routine schedule, with few supplementary actions taken in recognition of the need for rapidly enhancing population immunity. Vaccine packages mostly did not address the actual range of VPDs that likely accounted for substantial disease risk. CONCLUSIONS: This review suggests inconsistencies and inequities in vaccine provision to crisis-affected populations. A consistent, standardised and broader approach to vaccine use in crises is needed.

Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation.

The glucagon-like peptide-1 receptor (GLP-1R) has broad physiological roles and is a validated target for treatment of metabolic disorders. Despite recent advances in GLP-1R structure elucidation, detailed mechanistic understanding of how different peptides generate profound differences in G protein-mediated signalling is still lacking. Here we combine cryo-electron microscopy, molecular dynamics simulations, receptor mutagenesis and pharmacological assays, to interrogate the mechanism and consequences of GLP-1R binding to four peptide agonists; glucagon-like peptide-1, oxyntomodulin, exendin-4 and exendin-P5. These data reveal that distinctions in peptide N-terminal interactions and dynamics with the GLP-1R transmembrane domain are reciprocally associated with differences in the allosteric coupling to G proteins. In particular, transient interactions with residues at the base of the binding cavity correlate with enhanced kinetics for G protein activation, providing a rationale for differences in G protein-mediated signalling efficacy from distinct agonists.

Factors Influencing Military Personnel Utilizing Chaplains: A Literature Scoping Review.

Chaplains have been embedded in military settings for over a millennium. In recent years however, the decline in spiritual/religious (S/R) affiliation of military personnel across Western cultures has led to some commentators questioning the utilization of religious chaplains by defence personnel. This scoping review maps the literature on S/R and non-S/R factors that influence utilizing military chaplains-with a particular emphasis on the Australian military context. A systematic scoping review of tertiary literature databases using Arksey and O'Malley (2003) and Joanna Briggs Institute methodologies (JBI, 2021), revealed a total of 33 articles meeting the inclusion criteria. Results fell into three broad categories: (i) how personal religious views influence utilization of military chaplaincy, (ii) barriers and enablers to personnel utilizing military chaplains, and (iii) the impact of chaplaincy. Despite the current reduction in religiosity in Western society, findings from this scoping review suggest there is little evidence that low religiosity among military personnel forms a significant barrier to utilizing chaplaincy services. To the contrary, the literature revealed that chaplains provide trusted, confidential, and holistic support for military personnel that if diminished or compromised would leave a substantial gap in staff well-being services.

The Role and Value of Chaplains in the Ambulance Service: Paramedic Perspectives.

Chaplains are employed by ambulance services in many states across Australia as one element in a suite of initiatives to support the health and wellness of paramedics. The aim of this paper is to present key findings from a study that explored paramedic perspectives on the role and value of chaplains in the ambulance service. Seventeen paramedics participated in semi-structured interviews. Data were analysed using framework analysis. Two themes were identified: scope of the chaplain's role and organisational factors influencing the chaplain's role. Paramedics highly valued what they believed to be proactive and reactive support provided by ambulance chaplains, regardless of paramedics' personal spiritual or religious beliefs.

Development of AC265347-Inspired Calcium-Sensing Receptor Ago-Positive Allosteric Modulators.

The calcium-sensing receptor (CaSR) is a clinical target in the treatment of hyperparathyroidism and related diseases. However, clinical use of approved CaSR-targeting drugs such as cinacalcet is limited due to adverse side effects including hypocalcaemia, nausea and vomiting, and in some instances, a lack of efficacy. The CaSR agonist and positive allosteric modulator (ago-PAM), AC265347, is chemically distinct from clinically-approved CaSR PAMs. AC265347 potently suppressed parathyroid hormone (PTH) release in rats with a lower propensity to cause hypocalcaemia compared to cinacalcet and may therefore offer benefits over current CaSR PAMs. Here we report a structure activity relationship (SAR) study seeking to optimise AC265347 as a drug candidate and disclose the discovery of AC265347-like compounds with diverse pharmacology and improved physicochemical and drug-like properties.

Development of Covalent, Clickable Probes for Adenosine A1 and A3 Receptors.

Adenosine receptors are attractive therapeutic targets for multiple conditions, including ischemia-reperfusion injury and neuropathic pain. Adenosine receptor drug discovery efforts would be facilitated by the development of appropriate tools to assist in target validation and direct receptor visualization in different native environments. We report the development of the first bifunctional (chemoreactive and clickable) ligands for the adenosine A1 receptor (A1R) and adenosine A3 receptor (A3R) based on an orthosteric antagonist xanthine-based scaffold and on an existing structure-activity relationship. Bifunctional ligands were functional antagonists with nanomolar affinity and irreversible binding at the A1R and A3R. In-depth pharmacological profiling of these bifunctional ligands showed moderate selectivity over A2A and A2B adenosine receptors. Once bound to the receptor, ligands were successfully "clicked" with a cyanine-5 fluorophore containing the complementary "click" partner, enabling receptor detection. These bifunctional ligands are expected to aid in the understanding of A1R and A3R localization and trafficking in native cells and living systems.

Therapeutic Opportunities of Targeting Allosteric Binding Sites on the Calcium-Sensing Receptor.

The CaSR is a class C G protein-coupled receptor (GPCR) that acts as a multimodal chemosensor to maintain diverse homeostatic functions. The CaSR is a clinical therapeutic target in hyperparathyroidism and has emerged as a putative target in several other diseases. These include hyper- and hypocalcaemia caused either by mutations in the CASR gene or in genes that regulate CaSR signaling and expression, and more recently in asthma. The development of CaSR-targeting drugs is complicated by the fact that the CaSR possesses many different binding sites for endogenous and exogenous agonists and allosteric modulators. Binding sites for endogenous and exogenous ligands are located throughout the large CaSR protein and are interconnected in ways that we do not yet fully understand. This review summarizes our current understanding of CaSR physiology, signaling, and structure and how the many different binding sites of the CaSR may be targeted to treat disease.

Structure and dynamics of the CGRP receptor in apo and peptide-bound forms.

G protein-coupled receptors (GPCRs) are key regulators of information transmission between cells and organs. Despite this, we have only a limited understanding of the behavior of GPCRs in the apo state and the conformational changes upon agonist binding that lead to G protein recruitment and activation. We expressed and purified unmodified apo and peptide-bound calcitonin gene-related peptide (CGRP) receptors from insect cells to determine their cryo-electron microscopy (cryo-EM) structures, and we complemented these with analysis of protein conformational dynamics using hydrogen-deuterium exchange mass spectrometry and three-dimensional variance analysis of the cryo-EM data. Together with our previously published structure of the active, Gs-bound CGRP receptor complex, our work provides insight into the mechanisms of class B1 GPCR activation.

Development of Clickable Photoaffinity Ligands for Metabotropic Glutamate Receptor 2 Based on Two Positive Allosteric Modulator Chemotypes.

The metabotropic glutamate receptor 2 (mGlu2) is a transmembrane-spanning class C G protein-coupled receptor that is an attractive therapeutic target for multiple psychiatric and neurological disorders. A key challenge has been deciphering the contribution of mGlu2 relative to other closely related mGlu receptors in mediating different physiological responses, which could be achieved through the utilization of subtype selective pharmacological tools. In this respect, allosteric modulators that recognize ligand-binding sites distinct from the endogenous neurotransmitter glutamate offer the promise of higher receptor-subtype selectivity. We hypothesized that mGlu2-selective positive allosteric modulators could be derivatized to generate bifunctional pharmacological tools. Here we developed clickable photoaffinity probes for mGlu2 based on two different positive allosteric modulator scaffolds that retained similar pharmacological activity to parent compounds. We demonstrate successful probe-dependent incorporation of a commercially available clickable fluorophore using bioorthogonal conjugation. Importantly, we also show the limitations of using these probes to assess in situ fluorescence of mGlu2 in intact cells where significant nonspecific membrane binding is evident.

Differential contribution of metabotropic glutamate receptor 5 common allosteric binding site residues to biased allosteric agonism.

Allosteric modulators of metabotropic glutamate receptor subtype 5 (mGlu5) represent an attractive therapeutic strategy for multiple CNS disorders. Chemically distinct mGlu5 positive allosteric modulators (PAMs) that interact with a common binding site can demonstrate biased allosteric agonism relative to the orthosteric agonist, DHPG, when comparing activity in signaling assays such as IP1 accumulation, ERK1/2 phosphorylation (pERK1/2) and iCa2+ mobilization. However, the structural basis for such biased agonism is not well understood. Therefore, we evaluated biased allosteric agonism mediated by four mGlu5 PAM-agonists from diverse chemical scaffolds (i.e., DPFE, VU0409551, VU29, and VU0424465) for three measures of mGlu5 activation (i.e., iCa2+ mobilization, IP1 accumulation and ERK1/2 phosphorylation) at eight single-point mutations within the common allosteric binding pocket of mGlu5. In particular, mGlu5 allosteric site mutations had differential effects on the intrinsic efficacy of mGlu5 PAMs for multiple signaling pathways. Specifically, a loss of agonism for iCa2+ mobilization was evident for DPFE and VU0409551 for most mutants, whereas IP1 accumulation and ERK phosphorylation were retained, albeit with reduced maximal responses. Additionally, bias profiles between iCa2+ mobilization and IP1/ERK pathways remained similar to wild type for most mutants. However, W784A and A809G mutants lost bias between IP1 accumulation and ERK phosphorylation for VU0424465, whereas a loss of bias between iCa2+ mobilization and ERK1/2 phosphorylation was evident for F787A, S808A and A809G mutants. These data provide further insight into the structural requirements for allosteric agonism across multiple mGlu5-mediated signaling pathways. An understanding of mGlu5 biased agonism at a structural level may provide the foundation for rational structure-based design of biased allosteric ligands for the treatment of neurological disorders.

Probe dependence and biased potentiation of metabotropic glutamate receptor 5 is mediated by differential ligand interactions in the common allosteric binding site.

The metabotropic glutamate receptor 5 (mGlu5) is a promising therapeutic target for multiple CNS disorders. Recent mGlu5 drug discovery has focused on targeting binding sites within the mGlu5 7-transmembrane domain (7TM) that are topographically distinct from that of the endogenous ligand. mGlu5 primarily couples to Gq/11 proteins leading to mobilization of intracellular Ca2+ (iCa2+), but also activates iCa2+ independent signaling pathways, with biased agonism/modulation operative for multiple positive allosteric modulator (PAM) and PAM-agonist chemotypes. Although several residues within the common allosteric binding pocket are key determinants of PAM activity, how these residues affect biased modulation is unknown. The current study probed the molecular basis of mGlu5 PAM biased modulation. Modulation of mGlu5 activity by four chemically distinct mGlu5 PAMs (VU0424465, DPFE, VU29 and VU0409551) was assessed across two distinct receptor endpoints (iCa2+ mobilization and ERK1/2 phosphorylation) at mGlu5 receptors containing single-point mutations of allosteric binding pocket residues informed by computational modeling. Many mutations had differential effects on PAM affinity and cooperativity across signaling endpoints, resulting in gain or reversal of bias at the level of both affinity and functional cooperativity. Additionally, mutants had differential effects on functional cooperativity between the orthosteric ligands, DHPG and glutamate, and the PAMs, DPFE and VU29, but not VU0409551, indicating that probe dependence is linked to orthosteric agonists conferring activation states that differentially influence allosteric ligand-receptor interactions in a chemotype dependent fashion. Collectively, these data provide crucial insight into the residues that govern different activation states adopted by mGlu5 in order to signal via distinct intracellular pathways when co-bound by orthosteric agonists and PAMs.

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function.

The calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor that responds to multiple endogenous agonists and allosteric modulators, including divalent and trivalent cations, L-amino acids, γ-glutamyl peptides, polyamines, polycationic peptides, and protons. The CaSR plays a critical role in extracellular calcium (Ca2+ o) homeostasis, as demonstrated by the many naturally occurring mutations in the CaSR or its signaling partners that cause Ca2+ o homeostasis disorders. However, CaSR tissue expression in mammals is broad and includes tissues unrelated to Ca2+ o homeostasis, in which it, for example, regulates the secretion of digestive hormones, airway constriction, cardiovascular effects, cellular differentiation, and proliferation. Thus, although the CaSR is targeted clinically by the positive allosteric modulators (PAMs) cinacalcet, evocalcet, and etelcalcetide in hyperparathyroidism, it is also a putative therapeutic target in diabetes, asthma, cardiovascular disease, and cancer. The CaSR is somewhat unique in possessing multiple ligand binding sites, including at least five putative sites for the "orthosteric" agonist Ca2+ o, an allosteric site for endogenous L-amino acids, two further allosteric sites for small molecules and the peptide PAM, etelcalcetide, and additional sites for other cations and anions. The CaSR is promiscuous in its G protein-coupling preferences, and signals via Gq/11, Gi/o, potentially G12/13, and even Gs in some cell types. Not surprisingly, the CaSR is subject to biased agonism, in which distinct ligands preferentially stimulate a subset of the CaSR's possible signaling responses, to the exclusion of others. The CaSR thus serves as a model receptor to study natural bias and allostery. SIGNIFICANCE STATEMENT: The calcium-sensing receptor (CaSR) is a complex G protein-coupled receptor that possesses multiple orthosteric and allosteric binding sites, is subject to biased signaling via several different G proteins, and has numerous (patho)physiological roles. Understanding the complexities of CaSR structure, function, and biology will aid future drug discovery efforts seeking to target this receptor for a diversity of diseases. This review summarizes what is known to date regarding key structural, pharmacological, and physiological features of the CaSR.