39 research outputs found
Deletion of type VIII collagen reduces blood pressure, increases carotid artery functional distensibility and promotes elastin deposition
Arterial stiffening is a significant predictor of cardiovascular disease development and mortality. In elastic arteries, stiffening refers to the loss and fragmentation of elastic fibers, with a progressive increase in collagen fibers. Type VIII collagen (Col-8) is highly expressed developmentally, and then once again dramatically upregulated in aged and diseased vessels characterized by arterial stiffening. Yet its biophysical impact on the vessel wall remains unknown. The purpose of this study was to test the hypothesis that Col-8 functions as a matrix scaffold to maintain vessel integrity during extracellular matrix (ECM) development. These changes are predicted to persist into the adult vasculature, and we have tested this in our investigation. Through ou
The RGS2 Gene Product from a Candidate Hypertension Allele Shows Decreased Plasma Membrane Association and Inhibition of G q
Alternative Translation Initiation of Human Regulators of G-Protein Signaling-2 Yields a Set of Functionally Distinct Proteins
RGS4-Deficiency Alters Intracellular Calcium and PKA-Mediated Control of Insulin Secretion in Glucose-Stimulated Beta Islets
A number of diverse G-protein signaling pathways have been shown to regulate insulin secretion from pancreatic β-cells. Accordingly, regulator of G-protein signaling (RGS) proteins have also been implicated in coordinating this process. One such protein, RGS4, is reported to show both positive and negative effects on insulin secretion from β-cells depending on the physiologic context under which it was studied. We here use an RGS4-deficient mouse model to characterize previously unknown G-protein signaling pathways that are regulated by RGS4 during glucose-stimulated insulin secretion from the pancreatic islets. Our data show that loss of RGS4 results in a marked deficiency in glucose-stimulated insulin secretion during both phase I and phase II of insulin release in intact mice and isolated islets. These deficiencies are associated with lower cAMP/PKA activity and a loss of normal calcium surge (phase I) and oscillatory (phase II) kinetics behavior in the RGS4-deficient β-cells, suggesting RGS4 may be important for regulation of both Gαi and Gαq signaling control during glucose-stimulated insulin secretion. Together, these studies add to the known list of G-protein coupled signaling events that are controlled by RGS4 during glucose-stimulated insulin secretion and highlight the importance of maintaining normal levels of RGS4 function in healthy pancreatic tissues
Kv4.3-Encoded Fast Transient Outward Current Is Presented in Kv4.2 Knockout Mouse Cardiomyocytes
<div><p>Gradients of the fast transient outward K<sup>+</sup> current (I<sub>to,f</sub>) contribute to heterogeneity of ventricular repolarization in a number of species. Cardiac I<sub>to,f</sub> levels and gradients change notably with heart disease. Human cardiac I<sub>to,f</sub> appears to be encoded by the Kv4.3 pore-forming α-subunit plus the auxiliary KChIP2 β-subunit while mouse cardiac I<sub>to,f</sub> requires Kv4.2 and Kv4.3 α-subunits plus KChIP2. Regional differences in cardiac I<sub>to,f</sub> are associated with expression differences in Kv4.2 and KChIP2. Although I<sub>to,f</sub> was reported to be absent in mouse ventricular cardiomyocytes lacking the Kv4.2 gene (Kv4.2-/-) when short depolarizing voltage pulses were used to activate voltage-gated K<sup>+</sup> currents, in the present study, we showed that the use of long depolarization steps revealed a heteropodatoxin-sensitive I<sub>to,f</sub> (at ~40% of the wild-type levels). Immunohistological studies further demonstrated membrane expression of Kv4.3 in Kv4.2-/- cardiomyocytes. Transmural I<sub>to,f</sub> gradients across the left ventricular wall were reduced by ~3.5-fold in Kv4.2-/- heart, compared to wild-type. The I<sub>to,f</sub> gradient in Kv4.2-/- hearts was associated with gradients in KChIP2 mRNA expression while in wild-type there was also a gradient in Kv4.2 expression. In conclusion, we found that Kv4.3-based I<sub>to,f</sub> exists in the absence of Kv4.2, although with a reduced transmural gradient. Kv4.2-/- mice may be a useful animal model for studying Kv4.3-based I<sub>to,f</sub> as observed in humans.</p></div