Smooth muscle expresses the Iα and the Iβ isoforms of cGMP-dependent protein kinase I (cGKI). Inactivation of the murine cGKI gene prkg1 leads to multiple phenotypes and premature death at ≈6 weeks. ...We reconstituted mice with the cGKIα or -Iβ isozyme to test which isozyme was needed to support basic smooth muscle functions. Mice were generated by gene targeting. The cGKIα or the -Iβ coding sequences were placed under the control of the SM22α promoter to express either isoform selectively in smooth muscle cells (SM-Iα or SM-Iβ transgene). To generate smooth muscle–specific cGKIα or cGKIβ rescue mice, the SM-Iα or SM-Iβ transgenes were crossed on a cGKI genetic background. The levels of cGKIα or -Iβ expression were comparable to endogenous cGKI expression in wild-type aortic and intestinal smooth muscles. In cGKIα or -Iβ rescue mice, expression of the isozymes was not detectable in non–smooth muscle tissues and cells. Median survival time of the Iα and Iβ rescue mice was 52 weeks. Both isozymes mediated the 8-bromo-cGMP–induced relaxation of precontracted jejunum and aorta muscle strips. Activation of both isozymes reduced hormone- or K-induced Cai levels. The cGKIα and cGKIβ rescue mice did not show a significant difference in intestinal passage time of BaSO4 in comparison with wild-type animals. Telemetric blood pressure measurements in conscious freely moving animals did not show differences between rescues and control mice in basal blood pressure and its regulation by DETA-NO, sodium nitroprusside, carbachol, or Y-27632. These results show that cGKI in smooth muscle is essential and that either cGKI isozyme alone can rescue basic vascular and intestinal smooth muscle functions.
Aims Nitric oxide (NO) and atrial natriuretic peptide (ANP) signalling via cGMP controls smooth muscle tone. One important signalling pathway of cGMP-dependent protein kinase type I (cGKI) is ...mediated by IRAG (IP3 receptor associated cGKI substrate) which is highly expressed in smooth muscle tissues. To elucidate the role of IRAG for NO- and ANP-mediated smooth muscle tone regulation, cGKI localization, and for its possible function in blood pressure adjustment, we generated IRAG-knockout mice by targeted deletion of exon 3. Methods and results IRAG deletion prevented stable interaction of IP3 receptor type I (IP3RI) with cGKIβ determined by cGMP affinity chromatography. Confocal microscopy in vascular smooth muscle cells (VSMCs) showed that localization of cGKIβ and cGKIα did not change in absence of IRAG. NO-, ANP-, and cGMP-dependent relaxation of hormone-contracted aortic vessels and colon was significantly affected in IRAG-knockout mice. The suppression of cGMP-induced relaxation was not rescued by selective expression of cGKIβ in smooth muscle from cGKIβ-transgenic mice. NO-, ANP-, and cGMP-mediated inhibition of the hormone-induced increase in intracellular calcium concentration measured by Fura2 was suppressed in IRAG-deficient VSMC. Telemetric measurements revealed that IRAG-deficient animals exhibited normal basal tone, but were resistant to blood pressure reduction induced by lipopolysaccharide-treatment. Conclusion These findings indicate that signalling of cGKIβ via IRAG is an essential functional part for regulation of smooth muscle tone and of intracellular calcium by NO (exogenously applicated or endogenously synthesized) and by ANP. IRAG signalling does not modulate basal tone but might be important for blood pressure regulation under pathophysiological conditions.
ACTH-stimulated aldosterone secretion can be inhibited by atrio-natriuretic peptide/cGMP. The mechanism behind this modulation has been reported to involve cGMP-dependent activation of ...phosphodiesterase 2 (PDE2) and hydrolysis of cAMP. Recently it was reported that activation of cGMP-dependent protein kinase II (cGKII) stimulated aldosterone secretion in rat zona glomerulosa cells. The zona glomerulosa of the murine adrenal cortex expresses cGKII and PDE2. We used mice with a homozygous inactivation of the cGKII gene to investigate in vivo the potential role of this kinase in aldosterone secretion. Basal plasma renin and aldosterone levels were similar in wild-type and cGKII⁻/⁻ mice. In vivo injection of atrio-natriuretic peptide decreased ACTH-stimulated aldosterone secretion in wild-type mice, but had no effect in cGKII-deficient mice. These results support the view that cGKII modulates aldosterone secretion in the murine adrenal cortex.
Little is known so far about the actual benefits of digital platforms that mediate volunteer helpers with households facing care responsibilities.
This article presents the initial results of ...a survey conducted among placement agencies as part of a multistage organized interview study. The key question is what benefits do agencies ascribe to the services in their own organization for the users and on a societal or sociospatial level.
For the purpose of conducting explorative guideline-based interviews, four placement agencies were selected. Of these, two use a matching platform and two do not. The data were analyzed using content analysis methods.
The providers perceive advantages in efficiency, improvements in quality but also new possibilities for harnessing new helper clientele as important beneficial aspects of using digital placement platforms for their own organization. In terms of nurturing users' trust and acceptance, hybrid matching models appear to be particularly advantageous by deploying digital technologies and also enabling personal support in developing helping relationships. The findings also suggest that public welfare-oriented, quality-assured matching platforms can unfurl additional benefits at sociospatial and societal levels.
Besides beneficial aspects for organizations and users it was also possible to reconstruct potential benefits in relation to local care networks.
Zusammenfassung
Hintergrund
Über den tatsächlichen Nutzen digitaler Plattformangebote, die engagementbereite Personen an Haushalte mit Pflegeaufgaben vermitteln, ist bisher wenig bekannt.
Ziel
Der ...Beitrag stellt erste Ergebnisse einer Vermittlungsanbieterbefragung als Teil einer mehrstufig angelegten Interviewstudie vor. Im Zentrum steht zunächst die Frage, welche Nutzenaspekte Anbieter ihren Angeboten im Hinblick auf die eigene Organisation, die Nutzer:innen sowie auf gesellschaftlicher oder sozialräumlicher Ebene zuschreiben.
Material und Methoden
Für leitfadengestützte Interviews wurden Vermittlungsanbieter ausgewählt. Zwei davon nutzen eine Matching-Plattform, zwei nicht. Die Daten wurden über inhaltsanalytische Verfahren ausgewertet.
Ergebnisse
Effizienzvorteile, Qualitätsgewinne, aber auch neue Möglichkeiten zur Erschließung weiterer Helferklientele sind aus Anbietersicht wichtige Nutzenaspekte digitaler Matching-Plattformen für die eigene Organisation. Um Vertrauen und Akzeptanz aufseiten der Nutzenden zu fördern, erscheinen hybrid gestaltete Vermittlungsmodelle besonders vorteilhaft. Sie ermöglichen neben der Nutzung digitaler Technologien zugleich persönliche Begleitung im Aufbau von Hilfebeziehungen. Die Befunde legen zudem nahe, dass gemeinwohlorientierte, qualitätsgesicherte Vermittlungsplattformen auch auf sozialräumlicher Ebene Nutzenvorteile entfalten können.
Diskussion und Fazit
Neben Nutzenaspekten in Bezug auf die eigene Organisation und auf Nutzer:innen konnten auch nutzenstiftende Potenziale in Bezug auf lokale Sorgenetzwerke rekonstruiert werden.
cGMP Regulated Protein Kinases (cGK) Hofmann, Franz; Bernhard, Dominik; Lukowski, Robert ...
Handbook of experimental pharmacology,
2009
191
Book Chapter, Journal Article
Recenzirano
cGMP-dependent protein kinases (cGK) are serine/threonine kinases that are widely distributed in eukaryotes. Two genes — prkg1 and prkg2 — code for cGKs, namely cGKI and cGKII. In mammals, two ...isozymes, cGKIα and cGKIβ, are generated from the prkg1 gene. The cGKI isozymes are prominent in all types of smooth muscle, platelets, and specific neuronal areas such as cerebellar Purkinje cells, hippocampal neurons, and the lateral amygdala. The cGKII prevails in the secretory epithelium of the small intestine, the juxta-glomerular cells, the adrenal cortex, the chondrocytes, and in the nucleus suprachiasmaticus. Both cGKs are major downstream effectors of many, but not all signalling events of the NO/cGMP and the ANP/cGMP pathways. cGKI relaxes smooth muscle tone and prevents platelet aggregation, whereas cGKII inhibits renin secretion, chloride/water secretion in the small intestine, the resetting of the clock during early night, and endochondreal bone growth. cGKs are also modulators of cell growth and many other functions.
Phosphorylation of serine 1928 (Ser1928) of the cardiac Cav1.2 subunit of L-type Ca2+ channels has been proposed as the mechanism for regulation of L-type Ca2+ channels by protein kinase A (PKA). To ...test this directly in vivo, we generated a knock-in mouse with targeted mutation of Ser1928 to alanine. This mutation did not affect basal L-type current characteristics or regulation of the L-type current by PKA and the β-adrenergic receptor, whereas the mutation abolished phosphorylation of Cav1.2 by PKA. Therefore, our data show that PKA phosphorylation of Ser1928 of Cav1.2 is not functionally involved in β-adrenergic stimulation of Cav1.2-mediated Ca2+ influx into the cardiomyocyte.
S2k guideline: Rosacea Clanner‐Engelshofen, Benjamin M.; Bernhard, Dominik; Dargatz, Sonja ...
Journal der Deutschen Dermatologischen Gesellschaft,
August 2022, 2022-08-00, 20220801, Letnik:
20, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Summary
This updated and upgraded S2k guideline deals with the diagnosis and treatment of rosacea, which is a common, chronic inflammatory skin disease mostly affecting the face. Initially, rosacea ...is characterized by recurrent erythema, telangiectasia and flushing. Later, the inflammatory component predominates, with persistent erythema with follicular papules, papulopustules and pustules. The development of phyma, which usually occurs on the acral localizations, is the most severe manifestation. For the treatment of rosacea, the interdisciplinary guideline committee, with representatives of the German Dermatological Society (DDG), the Professional Association of German Dermatologists (BVDD), the German Opthalmological Society (DOG), the Society for Dermopharmacy (GD), the Swiss Society for Dermatology and Venereology (SGDV) and the German Rosacea Aid e. V., recommends the avoidance of trigger factors and topical applications of metronidazole, azelaic acid or ivermectin. For symptomatic treatment of persistent centrofacial erythema, the topical vasoconstrictors brimonidine or oxymetazoline can also be used. Systemic therapy is recommended for therapy‐resistant and severe forms of rosacea papulopustulosa. The drug of choice is low‐dose doxycycline. Alternatively, low‐dose isotretinoin can be recommended. Ocular rosacea should be treated with lid margin hygiene. For topical treatment, ciclosporin eye drops, azithromycin, ivermectin or metronidazole are suggested.
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