Ion channel mutations can cause distinct neuropsychiatric diseases. We first studied the biophysical and neurophysiological consequences of four mutations in the human Na+ channel gene SCN8A causing either mild (E1483K) or severe epilepsy (R1872W), or intellectual disability and autism without epilepsy (R1620L, A1622D). Only combined electrophysiological recordings of transfected wild-type or mutant channels in both neuroblastoma cells and primary cultured neurons revealed clear genotype-phenotype correlations. The E1483K mutation causing mild epilepsy showed no significant biophysical changes, whereas the R1872W mutation causing severe epilepsy induced clear gain-of-function biophysical changes in neuroblastoma cells. However, both mutations increased neuronal firing in primary neuronal cultures. In contrast, the R1620L mutation associated with intellectual disability and autism-but not epilepsy-reduced Na+ current density in neuroblastoma cells and expectedly decreased neuronal firing. Interestingly, for the fourth mutation, A1622D, causing severe intellectual disability and autism without epilepsy, we observed a dramatic slowing of fast inactivation in neuroblastoma cells, which induced a depolarization block in neurons with a reduction of neuronal firing. This latter finding was corroborated by computational modelling. In a second series of experiments, we recorded three more mutations (G1475R, M1760I, G964R, causing intermediate or severe epilepsy, or intellectual disability without epilepsy, respectively) that revealed similar results confirming clear genotype-phenotype relationships. We found intermediate or severe gain-of-function biophysical changes and increases in neuronal firing for the two epilepsy-causing mutations and decreased firing for the loss-of-function mutation causing intellectual disability. We conclude that studies in neurons are crucial to understand disease mechanisms, which here indicate that increased or decreased neuronal firing is responsible for distinct clinical phenotypes.
Copper (Cu) is an essential nutrient for plant growth and development. This metal serves as a constituent element or enzyme cofactor that participates in many biochemical pathways and plays a key role in photosynthesis, respiration, ethylene sensing, and antioxidant systems. The physiological significance of Cu uptake and compartmentalization in plants has been underestimated, despite the importance of Cu in cellular metabolic processes. As a micronutrient, Cu has low cellular requirements in plants. However, its bioavailability may be significantly reduced in alkaline or organic matter-rich soils. Cu deficiency is a severe and widespread nutritional disorder that affects plants. In contrast, excessive levels of available Cu in soil can inhibit plant photosynthesis and induce cellular oxidative stress. This can affect plant productivity and potentially pose serious health risks to humans via bioaccumulation in the food chain. Plants have evolved mechanisms to strictly regulate Cu uptake, transport, and cellular homeostasis during long-term environmental adaptation. This review provides a comprehensive overview of the diverse functions of Cu chelators, chaperones, and transporters involved in Cu homeostasis and their regulatory mechanisms in plant responses to varying Cu availability conditions. Finally, we identified that future research needs to enhance our understanding of the mechanisms regulating Cu deficiency or stress in plants. This will pave the way for improving the Cu utilization efficiency and/or Cu tolerance of crops grown in alkaline or Cu-contaminated soils.
Calcium-activator protein for secretion (CAPS) is a cytosolic protein that associates with large dense-core vesicles and is involved in their secretion. Mammals express two CAPS isoforms, which share a similar domain structure including a Munc13 homology domain that is believed to be involved in the priming of secretory vesicles. A variety of studies designed to perturb CAPS function indicate that CAPS is involved in the secretion of large dense-core vesicles, but where in the secretory pathway CAPS acts is still under debate. Mice in which one allele of the CAPS-1 gene is deleted exhibit a deficit in catecholamine secretion from chromaffin cells. We have examined catecholamine secretion from chromaffin cells in which both CAPS genes were deleted and show that the deletion of both CAPS isoforms causes a strong reduction in the pool of rapidly releasable chromaffin granules and of sustained release during ongoing stimulation. We conclude that CAPS is required for the adequate refilling and/or maintenance of a rapidly releasable granule pool.
As a scaffold protein, calcium/calmodulin-dependent serine protein kinase (CASK) has been extensively studied in a variety of tissues throughout the body. The
Abstract Frequency‐upconverted fluorescence and stimulated emission induced by multiphoton absorption (MPA) have attracted much interest. As compared with low‐order MPA processes, the construction of high‐order MPA processes is highly desirable and rather attractive, yet remains a formidable challenge due to its inherent low transition probability. We report the observation of the first experimental frequency‐upconverted fluorescence and stimulated emission by simultaneous six‐photon excitation in an organic molecular system. The well‐designed organic conjugated system based on cross‐shaped spiro‐fused ladder‐type oligo( p ‐phenylene)s (SpL− z , z =1–3) manifests reasonably high MPA cross‐sections and brilliant luminescence emission simultaneously. The six‐photon absorption cross‐section of SpL‐3 with an extended π‐conjugation was evaluated as 8.67×10 −169 cm 12 s 5 photon −5 . Exceptionally efficient 2‐ to 6‐photon excited stimulated emission was achieved under near‐infrared laser excitation.
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