Hyperpyrexia in the emergency department

McGugan, Elizabeth

doi:10.1046/j.1442-2026.2001.00189.x

Cited by 23 publications

(10 citation statements)

References 25 publications

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“…CLU is very heat stable and heating up to at least 60°C does not inhibit its chaperone action (9,12). Mammals experience sporadic increases in body temperature as a result of physical activity (31), environmental exposure (32), and infection (33); fevers of up to 42°C have been reported (34). Thus, the mild heat stress (41°C) used to induce the precipitation of CS is encountered physiologically.…”

Section: Discussionmentioning

confidence: 99%

Structural Characterization of Clusterin-Chaperone Client Protein Complexes

Wyatt

Yerbury

Wilson

2009

Journal of Biological Chemistry

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Clusterin (CLU) is a potent extracellular chaperone that inhibits protein aggregation and precipitation otherwise caused by physical or chemical stresses (e.g. heat, reduction). This action involves CLU forming soluble high molecular weight (HMW) complexes with the client protein. Other than their unquantified large size, the physical characteristics of these complexes were previously unknown. In this study, HMW CLUcitrate synthase (CS), HMW CLU-fibrinogen (FGN), and HMW CLU-glutathione S-transferase (GST) complexes were generated in vitro, and their structures studied using size exclusion chromatography (SEC), ELISA, SDS-PAGE, dynamic light scattering (DLS), bisANS fluorescence, and circular dichroism spectrophotometry (CD). Densitometry of Coomassie Blue-stained SDS-PAGE gels indicated that all three HMW CLU-client protein complexes had an approximate mass ratio of 1:2 (CLU:client protein). SEC indicated that all three clients formed complexes with CLU > 4 ؋ 10 7 Da; however, DLS estimated HMW CLU-FGN to have a diameter of 108.57 ؎ 18.09 nm, while HMW CLU-CS and HMW CLU-GST were smaller with estimated diameters of 51.06 ؎ 6.87 nm and 52.61 ؎ 7.71 nm, respectively. Measurements of bisANS fluorescence suggest that the chaperone action of CLU involves preventing the exposure to aqueous solvent of hydrophobic regions that are normally exposed by the client protein during heat-induced unfolding. CD analysis indicated that, depending on the individual client protein, CLU may interact with a variety of intermediates on protein unfolding pathways with different amounts of native secondary structure. In vivo, soluble complexes like those studied here are likely to serve as vehicles to dispose of otherwise dangerous aggregationprone misfolded extracellular proteins.Controlled unfolding is important in many biological processes including protein translocation, degradation by proteases, and regulation of enzyme activity. Uncontrolled unfolding and the consequent accumulation of insoluble protein aggregates is implicated in the pathology of many diseases including Alzheimer disease and type II diabetes and is promoted by various stresses such as oxidative stress (1), shear stress (2), and thermal stress (3). Cells have extensive quality control mechanisms to ensure that intracellular proteins are maintained predominantly in their native conformations. Molecular chaperones are known to play a central role in these systems by targeting unfolded proteins for refolding or degradation (4 -7). However, little is known about the existence of corresponding systems for protein folding quality control in the extracellular environment (8).A large number of alternative functions have been proposed for clusterin (CLU), 4 nevertheless, the potent chaperone activity of this protein (9 -13) and its constitutive presence in many biological fluids suggests that it is likely to be important in extracellular protein folding quality control. Recently haptoglobin (14) and ␣ 2 -macroglobulin (15, 16) have also been identified as extracellular ch...

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Section: Discussionmentioning

confidence: 99%

Structural Characterization of Clusterin-Chaperone Client Protein Complexes

Wyatt

Yerbury

Wilson

2009

Journal of Biological Chemistry

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“…6A, panel ii). Heat stresses used here (41°C) occur in vivo: during exercise, core temperatures can exceed 40°C (67) and muscle temperatures may reach 41°C (68), heat stroke is defined as temperatures exceeding 40.6°C (69), and during drug-induced fevers core temperatures may reach 42°C (70). Similarly, shear stress of 40 -60 dynes/cm 2 is physiologically relevant and simulates a degree of the variability present in human circulation: blood is constantly exposed to a variable arterial shear stress ϳ10 -70 dynes/cm 2 in health, although this ranges up to levels greater than 100 dynes/cm 2 in pathological states (71).…”

Section: Discussionmentioning

confidence: 99%

Serum Albumin Prevents Protein Aggregation and Amyloid Formation and Retains Chaperone-like Activity in the Presence of Physiological Ligands

Finn

Nunez

Sunde

et al. 2012

Journal of Biological Chemistry

132

101

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Background: Serum albumin is a highly abundant circulating protein and may have chaperone-like activity. Results: Serum albumin titratably inhibits aggregation and amyloid formation of client proteins and maintains chaperone-like activity under physiological conditions. Conclusion: The chaperone-like activity of serum albumin suggests it protects against protein misfolding and aggregation. Significance: This may have implications for protein misfolding disorders of the extracellular compartment.

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“…Increasingly, emergency medical facilities are faced with cases of hyperthermia associated with serotonin syndrome caused by the interaction of medications prescribed for mood disorder (McGugan, 2001). Interestingly, lethal hyperthermia is known to be a leading cause of death in patients taking monoamine oxidase inhibitors in response to the accumulation of high levels of serotonin in the synapse (Sporer, 1995).…”

Section: Discussionmentioning

confidence: 99%

Ambient Temperature Influences Core Body Temperature Response in Rat Lines Bred for Differences in Sensitivity to 8-Hydroxy-dipropylaminotetralin

Nicholas

Seiden²

2003

J Pharmacol Exp Ther

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Agonist-induced decrease in core body temperature has commonly been used as a measure of serotonin1A (5-HT 1A ) receptor sensitivity in mood disorder. The thermoregulatory basis for 5-HT 1A receptor agonist-induced temperature responses in humans and rats remains unclear. Therefore, the influence of ambient temperature on 5-HT 1A receptor-mediated decreases in core body temperature were measured in rat lines bred for high (HDS) or low (LDS) sensitivity to the selective 5-HT 1A receptor agonist 8-hydroxy-dipropylaminotetralin (8-OH-DPAT). HDS and LDS rats were injected with either saline, 0.25 or 0.50 mg/kg 8-OH-DPAT at ambient temperatures of 10.5, 24, 30, or 37.5°C, and core temperature was measured by radiotelemetry. For both lines, the thermic response to acute 8-OH-DPAT was greatest at 10.5°C and decreased in magnitude as ambient temperature increased to 30°C, consistent with hypothermia. HDS rats displayed a greater hypothermic response than LDS rats at 10.5, 24, and 30°C. At 37.5°C, LDS rats showed a lethal elevation of temperature in response to 0.50 mg/kg 8-OH-DPAT. All thermic responses to 8-OH-DPAT, including the lethality, were effectively blocked by pretreatment with the 5-HT 1A receptor antagonist WAY100635, suggesting line differences in thermoregulatory circuits that are influenced by 5-HT 1A receptor activation. Following repeated injection of 8-OH-DPAT, the magnitude of the hypothermic response decreased in both lines at 10.5°C, but increased in HDS rats treated with 0.50 mg/kg 8-OH-DPAT at 30 and 37.5°C. This pattern was reversed in HDS rats following 8-OH-DPAT challenge at 24°C, suggesting that a compensatory thermoregulatory response accounts for changes in the hypothermic response to chronic 8-OH-DPAT.

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Hyperpyrexia in the emergency department

Cited by 23 publications

References 25 publications

Structural Characterization of Clusterin-Chaperone Client Protein Complexes

Structural Characterization of Clusterin-Chaperone Client Protein Complexes

Serum Albumin Prevents Protein Aggregation and Amyloid Formation and Retains Chaperone-like Activity in the Presence of Physiological Ligands

Ambient Temperature Influences Core Body Temperature Response in Rat Lines Bred for Differences in Sensitivity to 8-Hydroxy-dipropylaminotetralin

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