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The relation of form and function, namely the impact of the synaptic anatomy on calcium dynamics in the presynaptic bouton, is a major challenge of present (computational) neuroscience at a cellular level. The Drosophila larval neuromuscular junction (NMJ) is a simple model system, which allows studying basic effects in a rather simple way. This synapse harbors several special structures. In particular, in opposite to standard vertebrate synapses, the presynaptic boutons are rather large, and they have several presynaptic zones. In these zones, different types of anatomical structures are present. Some of the zones bear a so-called T-bar, a particular anatomical structure. The geometric form of the T-bar resembles the shape of the letter "T" or a table with one leg. When an action potential arises, calcium influx is triggered. The probability of vesicle docking and neurotransmitter release is superlinearly proportional to the concentration of calcium close to the vesicular release site. It is tempting to assume that the T-bar causes some sort of calcium accumulation and hence triggers a higher release probability and thus enhances neurotransmitter exocytosis. In order to study this influence in a quantitative manner, we constructed a typical T-bar geometry and compared the calcium concentration close to the active zones (AZs). We compared the case of synapses with and without T-bars. Indeed, we found a substantial influence of the T-bar structure on the presynaptic calcium concentrations close to the AZs, indicating that this anatomical structure increases vesicle release probability. Therefore, our study reveals how the T-bar zone implies a strong relation between form and function. Our study answers the question of experimental studies (namely "Wichmann and Sigrist, Journal of neurogenetics 2010") concerning the sense of the anatomical structure of the T-bar., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Knodel, Dutta Roy and Wittum.)

Ca 2+ signals are probably the most common intracellular signaling cellular events, controlling an extensive range of responses in virtually all cells. Many cellular stimuli, often acting at cell surface receptors, evoke Ca 2+ signals by mobilizing Ca 2+ from intracellular stores. Inositol trisphosphate (IP 3 ) was the first messenger shown to link events at the plasma membrane to release Ca 2+ from the endoplasmic reticulum (ER), through the activation of IP 3 -gated Ca 2+ release channels (IP 3 receptors). Subsequently, two additional Ca 2+ mobilizing messengers were discovered, cADPR and NAADP. Both are metabolites of pyridine nucleotides, and may be produced by the same class of enzymes, ADP-ribosyl cyclases, such as CD38. Whilst cADPR mobilizes Ca 2+ from the ER by activation of ryanodine receptors (RyRs), NAADP releases Ca 2+ from acidic stores by a mechanism involving the activation of two pore channels (TPCs). In addition, other pyridine nucleotides have emerged as intracellular messengers. ADP-ribose and 2'-deoxy-ADPR both activate TRPM2 channels which are expressed at the plasma membrane and in lysosomes.

Astrocytes are a neural cell type critically involved in maintaining brain energy homeostasis as well as signaling. Like neurons, astrocytes are a heterogeneous cell population. Cortical astrocytes show a complex morphology with a highly branched aborization and numerous fine processes ensheathing the synapses of neighboring neurons, and typically extend one process connecting to blood vessels. Recent studies employing genetically encoded fluorescent calcium (Ca 2+ ) indicators have described 'spontaneous' localized Ca 2+ -transients in the astrocyte periphery that occur asynchronously, independently of signals in other parts of the cells, and that do not involve somatic Ca 2+ transients; however, neither it is known whether these Ca 2+ -microdomains occur at or near neuronal synapses nor have their molecular basis nor downstream effector(s) been identified. In addition to Ca 2+ microdomains, sodium (Na + ) transients occur in astrocyte subdomains, too, most likely as a consequence of Na + co-transport with the neurotransmitter glutamate, which also regulates mitochondrial movements locally - as do cytoplasmic Ca 2+ levels. In this review, we cover various aspects of these local signaling events and discuss how structural and biophysical properties of astrocytes might foster such compartmentation. Astrocytes metabolically interact with neurons by providing energy substrates to active neurons. As a single astrocyte branch covers hundreds to thousands of synapses, it is tempting to speculate that these metabolic interactions could occur localized to specific subdomains of astrocytes, perhaps even at the level of small groups of synapses. We discuss how astrocytic metabolism might be regulated at this scale and which signals might contribute to its regulation. We speculate that the astrocytic structures that light up transiently as Ca 2+ -microdomains might be the functional units of astrocytes linking signaling and metabolic processes to adapt astrocytic function to local energy demands. The understanding of these local regulatory and metabolic interactions will be fundamental to fully appreciate the complexity of brain energy homeostasis as well as its failure in disease and may shed new light on the controversy about neuron-glia bi-directional signaling at the tripartite synapse., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Activation of vascular endothelial small- (KCa2.3, SK3) or intermediate- (KCa3.1, IK1) conductance Ca(2+)-activated potassium channels induces vasorelaxation via an endothelium-derived hyperpolarization (EDH) pathway. Although the activation of SK3 and IK1 channels converges on EDH, their subcellular effects on signal transduction are different and not completely clear. In this study, a novel endothelium-specific SK3 knockout (SK3(-/-)) mouse model was utilized to specifically examine the contribution of SK3 channels to mesenteric artery vasorelaxation, endothelial Ca(2+) dynamics, and blood pressure. The absence of SK3 expression was confirmed using real-time quantitative PCR and Western blot analysis. Functional studies showed impaired EDH-mediated vasorelaxation in SK3(-/-) small mesenteric arteries. Immunostaining results from SK3(-/-) vessels confirmed the absence of SK3 and further showed altered distribution of transient receptor potential channels, type 4 (TRPV4). Electrophysiological recordings showed a lack of SK3 channel activity, while TRPV4-IK1 channel coupling remained intact in SK3(-/-) endothelial cells. Moreover, Ca(2+) imaging studies in SK3(-/-) endothelium showed increased Ca(2+) transients with reduced amplitude and duration under basal conditions. Importantly, SK3(-/-) endothelium lacked a distinct type of Ca(2+) dynamic that is sensitive to TRPV4 activation. Blood pressure measurements showed that the SK3(-/-) mice were hypertensive, and the blood pressure increase was further enhanced during the 12-h dark cycle when animals are most active. Taken together, our results reveal a previously unappreciated SK3 signaling microdomain that modulates endothelial Ca(2+) dynamics, vascular tone, and blood pressure., (Copyright © 2016 the American Physiological Society.)

The plasma membrane calcium ATPases (PMCAs) are ATP-driven primary ion pumps found in all eukaryotic cells. They are the major high-affinity calcium extrusion system for expulsion of Ca(2+) ions from the cytosol and help restore the low resting levels of intracellular [Ca(2+)] following the temporary elevation of Ca(2+) generated during Ca(2+) signaling. Due to their essential role in the maintenance of cellular Ca(2+) homeostasis they were initially thought to be "sump pumps" for Ca(2+) removal needed by all cells to avoid eventual calcium overload. The discovery of multiple PMCA isoforms and alternatively spliced variants cast doubt on this simplistic assumption, and revealed instead that PMCAs are integral components of highly regulated multi-protein complexes fulfilling specific roles in calcium-dependent signaling originating at the plasma membrane. Biochemical, genetic, and physiological studies in gene-manipulated and mutant animals demonstrate the important role played by specific PMCAs in distinct diseases including those affecting the peripheral and central nervous system, cardiovascular disease, and osteoporosis. Human PMCA gene mutations and allelic variants associated with specific disorders continue to be discovered and underline the crucial role of different PMCAs in particular cells, tissues and organs., (Copyright © 2015 Elsevier Inc. All rights reserved.)