The Journal of physiology
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The Journal of physiology · Oct 2020
ReviewAngiotensin converting enzyme 2 at the interface between renin-angiotensin system inhibition and coronavirus disease 2019.
The coronavirus disease 2019 (COVID-19) is the third major coronavirus outbreak of this century. Its aetiological agent, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), requires angiotensin converting enzyme 2 (ACE2) for cellular entry. ⋯ Current evidence of ACEI/ARB-ACE2 interaction as well as the effects of ACEIs/ARBs on viral-associated acute lung injury is summarized and discussed in this review. This review assesses the evidence gathered so far and highlights the research that needs to be done to help inform clinical decision making.
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The Journal of physiology · Jul 2017
ReviewThe plasticity of descending controls in pain: translational probing.
Descending controls, comprising pathways that originate in midbrain and brainstem regions and project onto the spinal cord, have long been recognised as key links in the multiple neural networks that interact to produce the overall pain experience. There is clear evidence from preclinical and clinical studies that both peripheral and central sensitisation play important roles in determining the level of pain perceived. Much emphasis has been put on spinal cord mechanisms in central excitability, but it is now becoming clear that spinal hyperexcitability can be regulated by descending pathways from the brain that originate from predominantly noradrenergic and serotonergic systems. ⋯ These descending pathways are altered in neuropathy and the effects of excess serotonin may now become inhibitory through activation of spinal 5-HT7 receptors. Conditioned pain modulation (CPM) is the human counterpart of DNIC and requires a descending control also. Back and forward translational studies between DNIC and CPM, gauged between bench and bedside, are key for the development of analgesic therapies that exploit descending noradrenergic and serotonergic control pathways.
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Specificity is a core principle of exercise training to promote the desired adaptations for maximising athletic performance. The principle of specificity of adaptation is underpinned by the volume, intensity, frequency and mode of contractile activity and is most evident when contrasting the divergent phenotypes that result after undertaking either prolonged endurance or resistance training. The molecular profiles that generate the adaptive response to different exercise modes have undergone intense scientific scrutiny. ⋯ Chronic training studies provide robust evidence that endurance exercise can attenuate muscle hypertrophy and strength but the mechanistic underpinning of this 'interference' effect with concurrent training is unknown. Moreover, despite the potential for several key regulators of muscle metabolism to explain an incompatibility in adaptation between endurance and resistance exercise, it now seems likely that multiple integrated, rather than isolated, effectors or processes generate the interference effect. Here we review studies of the molecular responses in skeletal muscle and evidence for the interference effect with concurrent training within the context of the specificity of training adaptation.
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The Journal of physiology · Sep 2015
ReviewChloride transporters and receptor-mediated endocytosis in the renal proximal tubule.
The reabsorptive activity of renal proximal tubule cells is mediated by receptor-mediated endocytosis and polarized transport systems that reflect final cell differentiation. Loss-of-function mutations of the endosomal chloride-proton exchanger ClC-5 (Dent's disease) cause a major trafficking defect in proximal tubule cells, associated with lysosomal dysfunction, oxidative stress and dedifferentiation/proliferation. A similar but milder defect is associated with mutations in CFTR (cystic fibrosis transmembrane conductance regulator). Vesicular chloride transport appears to be important for the integrity of the endolysosomal pathway in epithelial cells. ⋯ The epithelial cells lining the proximal tubules of the kidney reabsorb a large amount of filtered ions and solutes owing to receptor-mediated endocytosis and polarized transport systems that reflect final cell differentiation. Dedifferentiation of proximal tubule cells and dysfunction of receptor-mediated endocytosis characterize Dent's disease, a rare disorder caused by inactivating mutations in the CLCN5 gene that encodes the endosomal chloride-proton exchanger, ClC-5. The disease is characterized by a massive urinary loss of solutes (renal Fanconi syndrome), with severe metabolic complications and progressive renal failure. Investigations of mutations affecting the gating of ClC-5 revealed that the proximal tubule dysfunction may occur despite normal endosomal acidification. In addition to defective endocytosis, proximal tubule cells lacking ClC-5 show a trafficking defect in apical receptors and transporters, as well as lysosomal dysfunction and typical features of dedifferentiation, proliferation and oxidative stress. A similar but milder defect is observed in mouse models with defective CFTR, a chloride channel that is also expressed in the endosomes of proximal tubule cells. These data suggest a major role for endosomal chloride transport in the maintenance of epithelial differentiation and reabsorption capacity of the renal proximal tubule.
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Resurgent Na(+) current results from a distinctive form of Na(+) channel gating, originally identified in cerebellar Purkinje neurons. In these neurons, the tetrodotoxin-sensitive voltage-gated Na(+) channels responsible for action potential firing have specialized mechanisms that reduce the likelihood that they accumulate in fast inactivated states, thereby shortening refractory periods and permitting rapid, repetitive, and/or burst firing. Under voltage clamp, step depolarizations evoke transient Na(+) currents that rapidly activate and quickly decay, and step repolarizations elicit slower channel reopening, or a 'resurgent' current. ⋯ Following its initial discovery, resurgent Na(+) current has been found in nearly 20 types of neurons. Emerging research suggests that resurgent current is preferentially increased in a variety of clinical conditions associated with altered cellular excitability. Here we review the biophysical, molecular and structural mechanisms of resurgent current and their relation to the normal functions of excitable cells as well as pathophysiology.