Novel aspects of extracellular adenosine dynamics revealed by adenosine sensor cells

Adenosine modulates diverse physiological and pathological processes in the brain, including neuronal activities, blood flow, and inflammation. However, the mechanisms underlying the dynamics of extracellu-lar adenosine are not fully understood. We have recently developed a novel biosensor, called an adenosine sensor cell, and we have characterized the neuronal and astrocytic pathways for elevating extracellular adenosine. In this review, the physiological implications and therapeutic potential of the pathways revealed by the adenosine sensor cells are discussed. We propose that the multiple pathways regulating extracellular adenosine allow for the diverse functions of this neuromodulator, and their malfunctions cause various neurological and psychiatric disorders.     

Cloning and characterization of voltage‐gated calcium channel alpha1 subunits in Xenopus laevis during development

Voltage‐gated calcium channels play a critical role in regulating the Ca²⁺ activity that mediates many aspects of neural development, including neural induction, neurotransmitter phenotype specification, and neurite outgrowth. Using Xenopus laevis embryos, we describe the spatial and temporal expression patterns during development of the 10 pore‐forming alpha1 subunits that define the channels' kinetic properties. In situ hybridization indicates that Ca_V1.2, Ca_V2.1, Ca_V2.2, and Ca_V3.2 are expressed during neurula stages throughout the neural tube. These, along with Ca_V1.3 and Ca_V2.3, beginning at early tail bud stages, and Ca_V3.1 at late tail bud stages, are detected in complex patterns within the brain and spinal cord through swimming tadpole stages. Additional expression of various alpha1 subunits was observed in the cranial ganglia, retina, olfactory epithelium, pineal gland, and heart. The unique expression patterns for the different alpha1 subunits suggests they are under precise spatial and temporal regulation and are serving specific functions during embryonic development. Developmental Dynamics 238:2891–2902, 2009. © 2009 Wiley‐Liss, Inc.     

Analgesic properties of S100A9 C-terminal domain: a mechanism dependent on calcium channel inhibition

Calcium-binding protein S100A9 and its C-terminus peptide (mS100A9p) are anti-inflammatory and induce antinociception in rodents. We investigated the mechanisms involved in this effect, and whether they depend or not on the anti-inflammatory properties of mS100A9p. In mice, mS100A9p inhibited thermal and mechanical hyperalgesia and allodynia induced by either carrageenan or formalin, without interfering with paw edema. mS100A9p also inhibited myeloperoxidase activity (MPO), a marker of granulocyte infiltration, induced by carrageenan, but increased MPO after formalin intraplantar injection. The in vivo analgesic properties of mS100A9p were independent of opioid receptor activation. Calcium flux into dorsal root ganglia neurons induced by KCl was inhibited by mS100A9p, suggesting that this protein is able to inhibit signaling, in sensory neurons. The inhibitory effects of mS100A9p on primary afferent signaling were neither due to intracellular calcium store inhibition nor to calcium chelating properties. However, mS100A9p was able to inhibit calcium currents carried by transiently expressed N-type, but not L-type calcium channels, as demonstrated both by gene transfection techniques and electrophysiology. These data demonstrate that mS100A9p interferes with mechanisms involved in nociception, hyperalgesia and calcium signaling in sensory neurons, modulating primary afferent nociceptive signal by inhibiting activation of N-type voltage operated calcium channels.     

Effects of implant geometry, surface properties, and TGF-β1 on peri-implant bone response: an experimental study in goats

Objectives: Despite the high success rates in implantology, the desire to use oral implants in more challenging clinical situations drives the need for continuing refinements in implant design and surface properties. In the present study, the effect of implant geometry on implant bone response was evaluated using two geometrically different implant types, i.e. screw type (St) and push-in type(Pi). Furthermore, the potential beneficial effect of an electrosprayed calcium phosphate (CaP) coating, either or not enriched with the osteoinductive growth factor TGF-β1, on the osteogenic response was examined.
Material and methods: A total of 54 implants, divided into six groups ( n =9), were inserted into the femoral condyles of nine goats. After an implantation period of 12 weeks, retrieved specimens were evaluated histologically and histomorphometrically. Measurements were statistically evaluated using SPSS 14.0 and analyzed using a linear regression model.
Results: With respect to implant design, St-implants showed an overall superior biological healing response compared with Pi-implants. Considering surface properties, the deposition of an electrosprayed CaP (2–3 μm) coating onto implants significantly increased the amount of bone–implant contact for both implant types. Additional enrichment of the CaP coating with the osteoinductive growth factor TGF-β1 did not significantly affect peri-implant bone response.
Conclusions: The results of this study indicate that a substantial improvement of the osteogenic response to titanium implants can be achieved by the deposition of an electrosprayed CaP coating. The enrichment of the coating with 1 μg TGF-β1 has only a marginal effect.     

Pharmacotherapy of osteoporosis in postmenopausal women: focus on safety

The therapy of osteoporosis has made enormous strides in the last decade. There is now a range of interventions, each with its pros and cons. Calcium and vitamin D supplementation remain the foundation and have few safety issues. Bisphosphonates are widely used, though gastrointestinal tolerance is a problem with some oral preparations. Intravenous administration may circumvent this, although this introduces the smaller problem of acute phase reactions. The side effect profile of hormone replacement therapy (HRT) is still being delineated after 40 years of use, with substantial new information expected in the next few years. This will clarify its place in the medical management of the menopause. Raloxifene appears to have a superior safety profile to HRT, though its efficacy on bone may be less. While none of these options is suitable for everyone, the range of available therapies does mean that most patients can find an intervention that is effective and acceptable.     

Effects of Calcium Infusion on Gastric Secretion in Heidenhain Pouch Dogs

Calcium salts were infused against a background of stimulation by histamine or porcine gastrin or against the release of endogenous gastrin (feeding test). Raising the plasma calcium to values noted in clinical chronic hyperparathyroidism did not influence histamine-stimulated secretion but had a strong inhibitory action on gastrin-stimulated secretion. In the feeding tests (endogenous gastrin) the onset of secretion was delayed by calcium infusion.

The results of these experiments cannot be related directly to the problem of hyperparathyroidism, hypercalcemia, and peptic ulcer. The results do, however, indicate a difference in the stimulant actions of gastrin and histamine.     

Smooth Muscle‐Protein Translocation and Tissue Function

Smooth muscle (SM) tissue is a complex organization of multiple cell types and is regulated by numerous signaling molecules (neurotransmitters, hormones, cytokines, etc.). SM contractile function can be regulated via expression and distribution of the contractile and cytoskeletal proteins, and activation of any of the second messenger pathways that regulate them. Spatial‐temporal changes in the contractile, cytoskeletal or regulatory components of SM cells (SMCs) have been proposed to alter SM contractile activity. Ca²⁺ sensitization/desensitization can occur as a result of changes at any of these levels, and specific pathways have been identified at all of these levels. Understanding when and how proteins can translocate within the cytoplasm, or to‐and‐from the plasmalemma and the cytoplasm to alter contractile activity is critical. Numerous studies have reported translocation of proteins associated with the adherens junction and G protein‐coupled receptor activation pathways in isolated SMC systems. Specific examples of translocation of vinculin to and from the adherens junction and protein kinase C (PKC) and 17 kDa PKC‐potentiated inhibitor of myosin light chain phosphatase (CPI‐17) to and from the plasmalemma in isolated SMC systems but not in intact SM tissues are discussed. Using both isolated SMC systems and SM tissues in parallel to pursue these studies will advance our understanding of both the role and mechanism of these pathways as well as their possible significance for Ca²⁺ sensitization in intact SM tissues and organ systems. Anat Rec, 297:1734–1746, 2014. © 2014 Wiley Periodicals, Inc.     

Standing on the shoulders of giants: Understanding calcium and vitamin D requirements

The quote by Sir Isaac Newton, ‘If I have seen further it is by standing on ye sholders of Giants’ was the theme of the British Nutrition Foundation (BNF) Annual Lecture 2012. Illustrations of the seminal contributions of six ‘giants’ of nutrition science, chosen because of their links to the BNF and to vitamin and mineral research in Cambridge, were used to give a historical context to recent studies and controversies on calcium and vitamin D requirements, particularly focusing on rickets and maternal and child nutrition.