The Journal of Physiology

Cover image for Vol. 594 Issue 3

Edited By: David Paterson

Impact Factor: 5.037

ISI Journal Citation Reports © Ranking: 2014: 5/83 (Physiology); 41/252 (Neurosciences)

Online ISSN: 1469-7793

Associated Title(s): Experimental Physiology

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  • The roles of c-Jun NH2-terminal kinases (JNKs) in obesity and insulin resistance

    The roles of c‐Jun NH2‐terminal kinases (JNKs) in obesity and insulin resistance

    Macrophage JNK plays a critical role in the polarisation of macrophages to the M1, pro-inflammatory state, leading to enhanced production of pro-inflammatory factors such as IL-1β, TNFα and IL-6. These factors are likely to induce impaired glucose metabolism and insulin resistance in a number of ways. For example, macrophage JNK-dependent IL-6 production induces adipocyte lipolysis, resulting in enhanced liver glucose production (see text for details). JNK activation within adipocytes similarly increases IL-6 production, potentially impacting on systemic metabolism in a similar manner to that of macrophage JNK activation. The up-regulation of SOCS3 by JNK-dependent, adipocyte-derived IL-6 may also lead to hepatic insulin resistance.

  • Respiratory modulated sympathetic activity: a putative mechanism for developing vascular resistance?

    Respiratory modulated sympathetic activity: a putative mechanism for developing vascular resistance?

    Spikes arriving in the sympathetic terminal trigger the release of noradrenaline (NA; ①). Aa, during tonic stimulation (top trace) in Wistar rats, much of the released NA is cleared by the NA reuptake (RU) transporter (NET; ②). Some of the released NA binds to α1-adrenoreceptors (α1Rs) on the smooth muscle cell (SMC; ③) membrane, causing a contractile response. Ab, during recruitment of respiratory modulated bursting (top trace) of sympathetic activity in Wistar rats, there is less RU as it becomes saturated ([DOWNWARDS ARROW]RU) and so more NA is available ([UPWARDS ARROW][NA]) to bind to α1Rs, enhancing the contractile response ([UPWARDS ARROW]VR). B, Simms et al. () demonstrated that pre-hypertensive SH rats exhibit amplified respiratory modulated bursting (top trace) and greater increases in VR following reinstatement of this rhythm. This is consistent with the amplified bursts causing greater NET saturation ([DOWNWARDS ARROW][DOWNWARDS ARROW]RU), resulting in greater NA concentrations in the neuromuscular junction ([DOWNWARDS ARROW][DOWNWARDS ARROW][NA]), and therefore a much larger contractile response ([UPWARDS ARROW][UPWARDS ARROW]VR). Chronic vasoconstriction may also lead to inward remodelling of the blood vessels, as SMCs are rearranged around a smaller lumen (bottom; Intengan & Schiffrin ()). Together, this may contribute to the ontogenesis of hypertension in this strain. C, in the adult SH rat, NET is dysfunctional (crosses), as reported previously (Rumantir et al. ; Cabassi et al. ; Schlaich et al. ). Hence, the contractile response is no longer dependent on the stimulation pattern; the elevated synaptic NA concentration is prolonged in both bursting and tonic patterns (top traces) producing marked vasoconstriction. [UPWARDS ARROW]/[UPWARDS ARROW][UPWARDS ARROW] = increase/large increase; [DOWNWARDS ARROW]/[DOWNWARDS ARROW][DOWNWARDS ARROW] = decrease/large decrease; pre-hyp = pre-hypertensive; VR = vascular resistance; [NA] = neuromuscular junction NA concentration; RU = reuptake.

  • Fundamental role for the KCNE4 ancillary subunit in Kv7.4 regulation of arterial tone

    Fundamental role for the KCNE4 ancillary subunit in Kv7.4 regulation of arterial tone

    Aa–Af, representative fluorescence and transmitted light (insert) confocal mid-cell xy-sections of mesenteric artery myocytes probed with primary antibody combinations for KCNE4, Kv7.4 or Kv7.5 together with appropriate PLA probes. Red punctae indicate target proteins are in close proximity (<40 nm). Nuclei are shown in blue as defined by 4′,6-diamidino-2-phenylindole. B, quantification of the mean ± SEM number of PLA signals per mid-cell xy-section for each antibody combination and a no primary control (NPC). **P < 0.01 for Kv7.4 + KCNE4 vs. NPC with anti-rabbit (R) and anti-mouse (M) PLA probes and ***P < 0.001 for Kv7.5 + KCNE4 or Kv7.4 + Kv7.5 vs. NPC with anti-rabbit (R) and anti-goat (G) PLA probes, according to a one-way ANOVA, Tukey's multiple comparisons test. Scale bar = 10 μm.

  • Essential role of carbonic anhydrase XII in secretory gland fluid and HCO3− secretion revealed by disease causing human mutation

    Essential role of carbonic anhydrase XII in secretory gland fluid and HCO3− secretion revealed by disease causing human mutation

    A, localization of CA12 (red) and ZO1 (green) in dispersed parotid acini and ducts. B, x–y (upper panels) and z scan (lower panels, taken at the white line in the upper panels) images of MDCK cells transfected with mKate-CA12 (red) and GFP-NBCe1-B (green) (left image) or with mKate-CA12(E143K) and GFP-NBCe1-B (right panel). C, HEK cells transfected with CA12(N28,80A) (red) and stained for DAPI (blue). D, co-localization of CA12(E143K) (red) and the ER marker KDEL-CFP (blue) in transfected in HEK cells.

  • Gating modes of calcium-activated chloride channels TMEM16A and TMEM16B

    Gating modes of calcium‐activated chloride channels TMEM16A and TMEM16B

    mTMEM16A was modelled on nhTMEM16 (Brunner et al. ) as described by Yu et al. (). Alpha-helices are numbered and lines indicate the approximate location of the bilayer. A, the TMEM16A homodimer viewed from the centre of the lipid bilayer. One monomer is coloured pale brown and the other light grey. Atoms in the subunit on the right that are shown in space-filling representation have been studied by mutagenesis and shown to have a role in channel function. B, one TMEM16A monomer was rotated 70 deg around the y-axis and viewed from the bilayer. This view looks into the hydrophilic cleft described by Brunner et al. (). Red: channel vestibule residues G628–M632 and I636–Q637 (Yu et al. ); cyan: ionic selectivity residues K603, R621 and R787 (Peters et al. ); magenta: ionic selectivity residue K588 (Yang et al. ); green: calcium binding residues E702, E705, E734 and D738 (Yu et al. ; Tien et al. 2014); brown: channel gating and calcium sensitivity residues 444EEEEEAVK451 (Xiao et al. ; this study).

  • The roles of c‐Jun NH2‐terminal kinases (JNKs) in obesity and insulin resistance
  • Respiratory modulated sympathetic activity: a putative mechanism for developing vascular resistance?
  • Fundamental role for the KCNE4 ancillary subunit in Kv7.4 regulation of arterial tone
  • Essential role of carbonic anhydrase XII in secretory gland fluid and HCO3− secretion revealed by disease causing human mutation
  • Gating modes of calcium‐activated chloride channels TMEM16A and TMEM16B

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