Search Results (4)

Store-operated Ca²⁺ entry (SOCE) controls Ca²⁺ homeostasis and mediates multiple Ca²⁺-dependent signaling pathways and cellular processes. It relies on the concerted activity of the reticular Ca²⁺ sensor STIM1 and the plasma membrane Ca²⁺ channel ORAI1. STIM1 and ORAI1 gain-of-function (GoF) mutations induce SOCE overactivity and excessive Ca²⁺ influx, leading to tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK), two overlapping disorders characterized by muscle weakness and a variable occurrence of multi-systemic anomalies affecting spleen, skin, and platelets. To date, different STIM1 mouse models exist, but only a single ORAI1 mouse model with muscle-specific TAM/STRMK phenotype has been described, precluding a comparative analysis of the physiopathology in all affected tissues. Here, we generated and characterized mice harboring a prevalent ORAI1 TAM/STRMK mutation and we provide phenotypic, physiological, biochemical, and functional data. Examination of Orai1^V109M/+ mice revealed smaller size, spleen enlargement, reduced muscle force, and decreased platelet numbers. Morphological analyses of muscle sections evidenced the presence of tubular aggregates, the histopathological hallmark on biopsies from TAM/STRMK patients absent in all reported STIM1 models. Overall, Orai1^V109M/+ mice reliably recapitulate the human disorder and highlight the primary physiological defects caused by ORAI1 gain-of-function mutations. They also provide the possibility to investigate the formation of tubular aggregates and to develop a common therapy for different TAM/STRMK forms. Full article

The changes in intracellular free calcium (Ca²⁺) levels are one of the most widely regulators of cell function; therefore, calcium as a universal intracellular mediator is involved in very important human diseases and disorders. In many cells, Ca²⁺ inflow is mediated by store-operated calcium channels, and it is recognized that the store-operated calcium entry (SOCE) is mediated by the two partners: the pore-forming proteins Orai (Orai1-3) and the calcium store sensor, stromal interaction molecule (STIM1-2). Importantly, the Orai/STIM channels are involved in crucial cell signalling processes such as growth factors, neurotransmitters, and cytokines via interaction with protein tyrosine kinase coupled receptors and G protein-coupled receptors. Therefore, in recent years, the issue of Orai/STIM channels as a drug target in human diseases has received considerable attention. This review summarizes and highlights our current knowledge of the Orai/STIM channels in human diseases and disorders, including immunodeficiency, myopathy, tubular aggregate, Stormorken syndrome, York platelet syndrome, cardiovascular and metabolic disorders, and cancers, as well as suggesting these channels as drug targets for pharmacological therapeutic intervention. Moreover, this work will also focus on the pharmacological modulators of Orai/STIM channel complexes. Together, our thoughtful of the biology and physiology of the Orai/STIM channels have grown remarkably during the past three decades, and the next important milestone in the field of store-operated calcium entry will be to identify potent and selective small molecules as a therapeutic agent with the purpose to target human diseases and disorders for patient benefit. Full article

Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) form a clinical continuum associating progressive muscle weakness with additional multi-systemic anomalies of the bones, skin, spleen, and platelets. TAM/STRMK arises from excessive extracellular Ca²⁺ entry due to gain-of-function mutations in the Ca²⁺ sensor STIM1 or the Ca²⁺ channel ORAI1. Currently, no treatment is available. Here we assessed the therapeutic potential of ORAI1 downregulation to anticipate and reverse disease development in a faithful mouse model carrying the most common TAM/STRMK mutation and recapitulating the main signs of the human disorder. To this aim, we crossed Stim1^R304W/+ mice with Orai1^+/− mice expressing 50% of ORAI1. Systematic phenotyping of the offspring revealed that the Stim1^R304W/+Orai1^+/− mice were born with a normalized ratio and showed improved postnatal growth, bone architecture, and partly ameliorated muscle function and structure compared with their Stim1^R304W/+ littermates. We also produced AAV particles containing Orai1-specific shRNAs, and intramuscular injections of Stim1^R304W/+ mice improved the skeletal muscle contraction and relaxation properties, while muscle histology remained unchanged. Altogether, we provide the proof-of-concept that Orai1 silencing partially prevents the development of the multi-systemic TAM/STRMK phenotype in mice, and we also established an approach to target Orai1 expression in postnatal tissues. Full article

Store-operated Ca²⁺ entry (SOCE) is a ubiquitous mechanism regulating extracellular Ca²⁺ entry to control a multitude of Ca²⁺-dependent signaling pathways and cellular processes. SOCE relies on the concerted activity of the reticular Ca²⁺ sensor STIM1 and the plasma membrane Ca²⁺ channel ORAI1, and dysfunctions of these key factors result in human pathologies. STIM1 and ORAI1 gain-of-function (GoF) mutations induce excessive Ca²⁺ influx through SOCE over-activation, and cause tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK), two overlapping disorders characterized by muscle weakness and additional multi-systemic signs affecting growth, platelets, spleen, skin, and intellectual abilities. In order to investigate the pathophysiological effect of overactive SOCE on muscle function and structure, we combined transcriptomics with morphological and functional studies on a TAM/STRMK mouse model. Muscles from Stim1^R304W/+ mice displayed aberrant expression profiles of genes implicated in Ca²⁺ handling and excitation-contraction coupling (ECC), and in vivo investigations evidenced delayed muscle contraction and relaxation kinetics. We also identified signs of reticular stress and abnormal mitochondrial activity, and histological and respirometric analyses on muscle samples revealed enhanced myofiber degeneration associated with reduced mitochondrial respiration. Taken together, we uncovered a molecular disease signature and deciphered the pathomechanism underlying the functional and structural muscle anomalies characterizing TAM/STRMK. Full article