Abstract：
:Mitochondrial permeability transition pore (mPTP) opening plays a critical role in cardiac reperfusion injury and its prevention is cardioprotective. Tumour cell mitochondria usually have high levels of hexokinase isoform 2 (HK2) bound to their outer mitochondrial membranes (OMM) and HK2 binding to heart mitochondria has also been implicated in resistance to reperfusion injury. HK2 dissociates from heart mitochondria during ischaemia, and the extent of this correlates with the infarct size on reperfusion. Here we review the mechanisms and regulations of HK2 binding to mitochondria and how this inhibits mPTP opening and consequent reperfusion injury. Major determinants of HK2 dissociation are the elevated glucose-6-phosphate concentrations and decreased pH in ischaemia. These are modulated by the myriad of signalling pathways implicated in preconditioning protocols as a result of a decrease in pre-ischaemic glycogen content. Loss of mitochondrial HK2 during ischaemia is associated with permeabilization of the OMM to cytochrome c, which leads to greater reactive oxygen species production and mPTP opening during reperfusion. Potential interactions between HK2 and OMM proteins associated with mitochondrial fission (e.g. Drp1) and apoptosis (B-cell lymphoma 2 family members) in these processes are examined. Also considered is the role of HK2 binding in stabilizing contact sites between the OMM and the inner membrane. Breakage of these during ischaemia is proposed to facilitate cytochrome c loss during ischaemia while increasing mPTP opening and compromising cellular bioenergetics during reperfusion. We end by highlighting the many unanswered questions and discussing the potential of modulating mitochondrial HK2 binding as a pharmacological target.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Halestrap AP,Pereira GC,Pasdois Pdoi
10.1111/bph.12899subject
Has Abstractpub_date
2015-04-01 00:00:00pages
2085-100issue
8eissn
0007-1188issn
1476-5381journal_volume
172pub_type
杂志文章,评审abstract：BACKGROUND AND PURPOSE:Proteinase activated receptor 2 (PAR2) is a GPCR associated with inflammation, metabolism and disease. Clues to understanding how to block PAR2 signalling associated with disease without inhibiting PAR2 activation in normal physiology could be provided by studies of biased signalling. EXPERIMENT...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/bph.12757
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journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1993.tb13864.x
更新日期：1993-10-01 00:00:00
abstract：:1. The anti-inflammatory effect of alpha-trinositol (D-myo-inositol-1,2,6-trisphosphate) on oedema formation, microvascular protein leakage and interstitial fluid pressure (Pif) in rat skin after frostbite injury, was investigated. Alpha-trinositol (40 mg kg body weight(-1)) was administered intravenously as a bolus b...
journal_title：British journal of pharmacology
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doi：10.1038/sj.bjp.0702442
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abstract：:1. Despite the observation of pharmacological responses to neuropeptide Y (NPY) in mammalian kidneys, there are species differences in the ease with which specific NPY binding sites can be demonstrated; we have investigated whether this can be explained by differential metabolism of NPY by a membrane-bound peptidase. ...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1991.tb12429.x
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abstract：:1. Acute SR 58611A (0.25 mg kg-1), was effective in reducing the blood glucose response to a glucose tolerance test (GTT) in normal lean (control) and spontaneously obese/diabetic CBA/Ca mice and to be equipotent to 1.25 mg kg-1 glibenclamide in lean mice. 2. Neither brown (BAT) nor white (WAT) adipose tissue lipogene...
journal_title：British journal of pharmacology
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doi：10.1038/sj.bjp.0702946
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doi：10.1038/sj.bjp.0700933
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abstract：BACKGROUND AND PURPOSE:Hydrogen sulphide reduces uterine contractility and is of potential interest as a treatment for uterine disorders. The aim of this study was to explore the mechanism of sodium sulphide (Na2 S)-induced relaxation of rat uterus, investigate the importance of redox effects and ion channel-mediated m...
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doi：10.1111/bph.13161
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abstract：:1. The receptor for glucagon-like peptide-1 (GLP-1) can be activated by both its physiological hormone and a peptide discovered in the venom of the Gila Monster, exendin-4, which shows promise as an antidiabetic agent. 2. Exendin-4 displays receptor-binding properties not observed for GLP-1. Firstly, exendin-4 can be ...
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doi：10.1038/sj.bjp.0705453
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journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1984.tb16461.x
更新日期：1984-05-01 00:00:00
abstract：:1 In the isolated kidney of the rabbit perfused with oxygenated Tyrode solution, we studied the effect of bradykinin on the vasoconstriction evoked by sympathetic nerve stimulation (3Hz, 1 ms) and by injections of noradrenaline (50 to 75 ng) in the presence and in the absence of indomethacin (1 microgram/ml), an inhib...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1979.tb08676.x
更新日期：1979-10-01 00:00:00
abstract：:1. The bovine pulmonary vein contracts in response to acetylcholine, histamine, 5-hydroxytryptamine and bradykinin. The tissue is particularly sensitive to 5-hydroxytryptamine (>0.1 ng/ml). Specific Schultz-Dale reactions were elicited in the pulmonary vein in response to horse plasma.2. The Schultz-Dale reaction is i...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：
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journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1980.tb10422.x
更新日期：1980-02-01 00:00:00
abstract：BACKGROUND AND PURPOSE:Obesity is a risk factor for several inflammation-based diseases including arthritis. We investigated the anti-nociceptive and anti-inflammatory effects of the cannabinoid CB1 receptor antagonist rimonabant in lean and diet-induced obese female rats with arthritis induced by complete Freund's adj...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0707138
更新日期：2007-03-01 00:00:00
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journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1968.tb07957.x
更新日期：1968-09-01 00:00:00
abstract：:1. The aim of this study was to determine the conditions under which the alpha2-adrenoceptor agonist UK14304 produces vasoconstriction in the porcine isolated ear artery. 2. UK14304 (0.3 microM) produced a small contraction of porcine isolated ear arteries which was 7.8+/-3.3% of the response to 60 mM KCl. Similar siz...
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更新日期：1998-07-01 00:00:00
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更新日期：2009-12-01 00:00:00
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journal_title：British journal of pharmacology
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更新日期：2014-12-01 00:00:00
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更新日期：2015-04-01 00:00:00
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journal_title：British journal of pharmacology
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journal_title：British journal of pharmacology
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更新日期：2018-09-01 00:00:00
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pub_type： 杂志文章,评审
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更新日期：2014-02-01 00:00:00
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journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1989.tb11948.x
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pub_type： 杂志文章
doi：10.1111/j.1476-5381.1990.tb15825.x
更新日期：1990-07-01 00:00:00
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pub_type： 杂志文章
doi：10.1038/sj.bjp.0703838
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pub_type： 杂志文章
doi：10.1038/sj.bjp.0701844
更新日期：1998-05-01 00:00:00
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journal_title：British journal of pharmacology
pub_type： 杂志文章
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更新日期：1986-03-01 00:00:00
abstract：:1. The effect of a single injection of the monoamine oxidase inhibitor, tranylcypromine, administered intravenously (20 mg/kg) or into the lateral cerebral ventricle (5-10 mg), on hypothalamic and rectal temperature, has been investigated.2. Intravenous tranylcypromine causes a significant rise in body temperature, wh...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1970.tb10594.x
更新日期：1970-05-01 00:00:00
abstract：:HMG-CoA reductase inhibitors (statins) have now become one of the most powerful pharmacological strategies in the treatment of cardiovascular diseases. Originally, the cardioprotective effects of statins were thought to be mediated through lipid lowering actions. However, it has now become increasingly clear that the ...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0706863
更新日期：2006-10-01 00:00:00
