Molecular regulation of calcium-sensing receptor (CaSR)-mediated signaling.

Calcium-sensing receptor (CaSR), a family C G-protein-coupled receptor, plays a crucial role in regulating calcium homeostasis by sensing small concentration changes of extracellular Ca2+, Mg2+, amino acids (e.g., L-Trp and L-Phe), small peptides, anions (e.g., HCO3 - and PO4 3-), and pH. CaSR-mediated intracellular Ca2+ signaling regulates a diverse set of cellular processes including gene transcription, cell proliferation, differentiation, apoptosis, muscle contraction, and neuronal transmission. Dysfunction of CaSR with mutations results in diseases such as autosomal dominant hypocalcemia, familial hypocalciuric hypercalcemia, and neonatal severe hyperparathyroidism. CaSR also influences calciotropic disorders, such as osteoporosis, and noncalciotropic disorders, such as cancer, Alzheimer's disease, and pulmonary arterial hypertension. This study first reviews recent advances in biochemical and structural determination of the framework of CaSR and its interaction sites with natural ligands, as well as exogenous positive allosteric modulators and negative allosteric modulators. The establishment of the first CaSR protein-protein interactome network revealed 94 novel players involved in protein processing in endoplasmic reticulum, trafficking, cell surface expression, endocytosis, degradation, and signaling pathways. The roles of these proteins in Ca2+-dependent cellular physiological processes and in CaSR-dependent cellular signaling provide new insights into the molecular basis of diseases caused by CaSR mutations and dysregulated CaSR activity caused by its protein interactors and facilitate the design of therapeutic agents that target CaSR and other family C G-protein-coupled receptors.

Structural Aspects and Prediction of Calmodulin-Binding Proteins.

Calmodulin (CaM) is an important intracellular protein that binds Ca2+ and functions as a critical second messenger involved in numerous biological activities through extensive interactions with proteins and peptides. CaM's ability to adapt to binding targets with different structures is related to the flexible central helix separating the N- and C-terminal lobes, which allows for conformational changes between extended and collapsed forms of the protein. CaM-binding targets are most often identified using prediction algorithms that utilize sequence and structural data to predict regions of peptides and proteins that can interact with CaM. In this review, we provide an overview of different CaM-binding proteins, the motifs through which they interact with CaM, and shared properties that make them good binding partners for CaM. Additionally, we discuss the historical and current methods for predicting CaM binding, and the similarities and differences between these methods and their relative success at prediction. As new CaM-binding proteins are identified and classified, we will gain a broader understanding of the biological processes regulated through changes in Ca2+ concentration through interactions with CaM.

A Meta-Analysis to Determine if Lower Extremity Muscle Strengthening Should Be Included in Military Knee Overuse Injury-Prevention Programs.

CONTEXT: Knee overuse injuries are the most common musculoskeletal complaints in military trainees and are common in active-duty warfighters. Muscle strengthening is usually recommended; however, research is conflicting in this area, which makes it difficult to develop effective screening, prevention, and training interventions for warfighters. OBJECTIVE: To determine if lower extremity muscular weakness contributes to knee overuse injuries and identify specific muscular involvement. DATA SOURCES: We searched MEDLINE, PubMed, Web of Science, SPORTDiscus, CINAHL, and Military & Government Collection and reference lists of relevant articles published between January 1, 2000, and January 1, 2013. STUDY SELECTION: For inclusion, requirements were uninjured and injured groups; provision of the sample size, means, and standard deviations for all groups; identification of the specific muscles assessed; and clearly defined knee injury. DATA EXTRACTION: Sample size, sex, and muscle strength means and standard deviations. DATA SYNTHESIS: Twenty-five studies met these criteria. We used the Scottish Intercollegiate Guidelines Network algorithm to determine the appropriate tool for appraising article quality. Unweighted random-effects model meta-analyses were conducted. Separate meta-analyses were performed for the moderators of strength measurement scale (absolute or normalized muscle strength), muscle group, and sex. A weighted random-effects model with a Hedges g effect metric and 95% confidence intervals were used for comparison across studies. CONCLUSIONS: Our meta-analysis suggests that individuals with symptoms of a knee overuse injury have lower absolute and normalized hip muscle strength. Specifically, they had lower absolute hip external-rotator, knee-extensor, and knee-flexor strength, as well as lower normalized hip external-rotator, hip-extensor, and hip-abductor strength, compared with asymptomatic control participants. The findings suggest a possible link between lower hip and thigh strength and knee overuse injuries. Further research is needed to determine if weakness is a cause or a result of knee overuse injuries before screening and intervention can be developed for at-risk warfighters.