Aminoglycoside antibiotics induce pH-sensitive activation of the calcium-sensing receptor

McLarnon, Stuart; Holden, D.; Ward, Donald T.; Jones, Malcolm N.; Elliott, A.; Riccardi, Daniela

doi:10.1016/s0006-291x(02)02133-2

Cited by 67 publications

(48 citation statements)

References 18 publications

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“…The impact of positive charge on spermine activation is not surprising given the observation that spermidine and putrescine are much less effective agonists for the CaR. As seen by us (data not shown) and described by others (19,20), neomycin activation of the CaR shows sim- ilar modulation by external pH, with acidic pH greatly reducing the concentration of neomycin needed for half-maximal stimulation of the CaR, probably because of the extent of protonation of its amine groups (data not shown).…”

Section: Effect Of External Ph On Car Activation By Polycationicsupporting

confidence: 79%

pH Sensing by the Calcium-sensing Receptor

Quinn

Bai

Brown

2004

Journal of Biological Chemistry

129

107

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The calcium-sensing receptor (CaR) is activated by small changes in the ionic extracellular calcium concentration (Ca o ) within the physiological range, allowing the parathyroid gland to regulate serum Ca o ; however, the CaR is also distributed in a number of other tissues where it may sense other endogenous agonists and modulators. CaR agonists are polycationic molecules, and our previous studies suggest that charged residues in the extracellular domain of the CaR are critical for receptor activation through electrostatic interactions. Therefore, pH could also potentially modulate CaR activation by its polycationic agonists. Changes in the concentration of extracellular H ؉ substantially altered the activation of the CaR by Ca o and other CaR agonists. The effects of external pH on the CaR's sensitivity to its agonists were observed for both acidic and basic deviations from physiological pH of 7.4, with increases in pH rendering the receptor more sensitive to activation by Ca o and decreases in pH producing the converse effect. At pH values more acidic than 5.5, CaR sensitivity to its agonists showed some recovery. Changes in the intracellular pH could not account for the effects of external pH on CaR sensitivity to its agonists. Other G-proteincoupled receptors, which are endogenously expressed in human embryonic kidney 293 cells, showed little change in activity with alterations in external pH or effects opposite those found for the CaR. Extracellular pH directly alters the CaR in the case of Ca o and Mg o activation; however, the charges on many organic and inorganic agonists are pH-dependent. Activating CaR mutations show reduced pH o modulation, suggesting a molecular mechanism for increased CaR activity at physiological pH o . Several CaR-expressing tissues, including regions of the stomach, the kidney, bone, and the brain, could potentially use the CaR as a sensor for pH and acid-base status.

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Section: Effect Of External Ph On Car Activation By Polycationicsupporting

confidence: 79%

pH Sensing by the Calcium-sensing Receptor

Quinn

Bai

Brown

2004

Journal of Biological Chemistry

129

107

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“…It has been hypothesized that gentamicin activates the CaSR in this area and in the distal convoluted tubule [168][169][170]. Under physiological conditions, the increased serum Ca 2+ levels stimulate this receptor and decrease the active reabsorption of Na + .…”

Section: Aminoglycosidesmentioning

confidence: 99%

Drug-induced acid-base disorders

et al. 2014

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The incidence of acid-base disorders (ABDs) is high, especially in hospitalized patients. ABDs are often indicators for severe systemic disorders. In everyday clinical practice, analysis of ABDs must be performed in a standardized manner. Highly sensitive diagnostic tools to distinguish the various ABDs include the anion gap and the serum osmolar gap. Drug-induced ABDs can be classified into five different categories in terms of their pathophysiology: (1) metabolic acidosis caused by acid overload, which may occur through accumulation of acids by endogenous (e.g., lactic acidosis by biguanides, propofol-related syndrome) or exogenous (e.g., glycol-dependant drugs, such as diazepam or salicylates) mechanisms or by decreased renal acid excretion (e.g., distal renal tubular acidosis by amphotericin B, nonsteroidal antiinflammatory drugs, vitamin D); (2) base loss: proximal renal tubular acidosis by drugs (e.g., ifosfamide, aminoglycosides, carbonic anhydrase inhibitors, antiretrovirals, oxaliplatin or cisplatin) in the context of Fanconi syndrome; (3) alkalosis resulting from acid and/or chloride loss by renal (e.g., diuretics, penicillins, aminoglycosides) or extrarenal (e.g., laxative drugs) mechanisms; (4) exogenous bicarbonate loads: milk-alkali syndrome, overshoot alkalosis after bicarbonate therapy or citrate administration; and (5) respiratory acidosis or alkalosis resulting from drug-induced depression of the respiratory center or neuromuscular impairment (e.g

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“…CaR activation is also enhanced by amino acids including phenylalanine (5) or the peptide glutathione (6), which bind within the extracellular domain and synergize with extracellular Ca 2ϩ . Polycationic aminoglycoside antibiotics including neomycin, gentamycin, and tobramycin activate CaR in the presence of Ca 2ϩ (5,7), and may contribute to nephrotoxicity in some patients treated for Gram-negative infections (8). Finally, phenylalkylamine derivatives represent a group of clinically important allosteric drugs for treatment of disorders of bone and mineral metabolism, including osteoporosis and hyperparathyroidism (9).…”

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confidence: 99%