Inflammation up-regulates cochlear expression of TRPV1 to potentiate drug-induced hearing loss.

Aminoglycoside antibiotics are essential for treating life-threatening bacterial infections, despite the risk of lifelong hearing loss. Infections induce inflammation and up-regulate expression of candidate aminoglycoside-permeant cation channels, including transient receptor potential vanilloid-1 (TRPV1). Heterologous expression of TRPV1 facilitated cellular uptake of (fluorescently tagged) gentamicin that was enhanced by agonists, and diminished by antagonists, of TRPV1.

Aminoglycoside-Induced Cochleotoxicity: A Review.

Aminoglycoside antibiotics are used as prophylaxis, or urgent treatment, for many life-threatening bacterial infections, including tuberculosis, sepsis, respiratory infections in cystic fibrosis, complex urinary tract infections and endocarditis. Although aminoglycosides are clinically-essential antibiotics, the mechanisms underlying their selective toxicity to the kidney and inner ear continue to be unraveled despite more than 70 years of investigation. The following mechanisms each contribute to aminoglycoside-induced toxicity after systemic administration: (1) drug trafficking across endothelial and epithelial barrier layers; (2) sensory cell uptake of these drugs; and (3) disruption of intracellular physiological pathways.

An integrated view of cisplatin-induced nephrotoxicity and ototoxicity.

Cisplatin is one of the most widely-used drugs to treat cancers. However, its nephrotoxic and ototoxic side-effects remain major clinical limitations. Recent studies have improved our understanding of the molecular mechanisms of cisplatin-induced nephrotoxicity and ototoxicity.

Diverse Kir expression contributes to distinct bimodal distribution of resting potentials and vasotone responses of arterioles.

The resting membrane potential (RP) of vascular smooth muscle cells (VSMCs) is a major determinant of cytosolic calcium concentration and vascular tone. The heterogeneity of RPs and its underlying mechanism among different vascular beds remain poorly understood. We compared the RPs and vasomotion properties between the guinea pig spiral modiolar artery (SMA), brain arterioles (BA) and mesenteric arteries (MA).

Sodium-glucose transporter-2 (SGLT2; SLC5A2) enhances cellular uptake of aminoglycosides.

Aminoglycoside antibiotics, like gentamicin, continue to be clinically essential worldwide to treat life-threatening bacterial infections. Yet, the ototoxic and nephrotoxic side-effects of these drugs remain serious complications. A major site of gentamicin uptake and toxicity resides within kidney proximal tubules that also heavily express electrogenic sodium-glucose transporter-2 (SGLT2; SLC5A2) in vivo.

Disruption of striatal-enriched protein tyrosine phosphatase (STEP) function in neuropsychiatric disorders.

Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific tyrosine phosphatase that plays a major role in the development of synaptic plasticity. Recent findings have implicated STEP in several psychiatric and neurological disorders, including Alzheimer's disease, schizophrenia, fragile X syndrome, Huntington's disease, stroke/ischemia, and stress-related psychiatric disorders. In these disorders, STEP protein expression levels and activity are dysregulated, contributing to the cognitive deficits that are present.

Identification of cisplatin-binding proteins using agarose conjugates of platinum compounds.

Cisplatin is widely used as an antineoplastic drug, but its ototoxic and nephrotoxic side-effects, as well as the inherent or acquired resistance of some cancers to cisplatin, remain significant clinical problems. Cisplatin's selectivity in killing rapidly proliferating cancer cells is largely dependent on covalent binding to DNA via cisplatin's chloride sites that had been aquated. We hypothesized that cisplatin's toxicity in slowly proliferating or terminally differentiated cells is primarily due to drug-protein interactions, instead of drug-DNA binding.

Bumetanide hyperpolarizes madin-darby canine kidney cells and enhances cellular gentamicin uptake by elevating cytosolic Ca(2+) thus facilitating intermediate conductance Ca(2+)--activated potassium channels.

Loop diuretics such as bumetanide and furosemide enhance aminoglycoside ototoxicity when co-administered to patients and animal models. The underlying mechanism(s) is poorly understood. We investigated the effect of these diuretics on cellular uptake of aminoglycosides, using Texas Red-tagged gentamicin (GTTR), and intracellular/whole-cell recordings of Madin-Darby canine kidney (MDCK) cells.

Intracellular mechanisms of aminoglycoside-induced cytotoxicity.

Since introduction into clinical practice over 60 years ago, aminoglycoside antibiotics remain important drugs in the treatment of bacterial infections, cystic fibrosis and tuberculosis. However, the ototoxic and nephrotoxic properties of these drugs are still a major clinical problem. Recent advances in molecular biology and biochemistry have begun to uncover the intracellular actions of aminoglycosides that lead to cytotoxicity.

Calreticulin binds to gentamicin and reduces drug-induced ototoxicity.

Aminoglycosides like gentamicin are among the most commonly used antibiotics in clinical practice and are essential for treating life-threatening tuberculosis and Gram-negative bacterial infections. However, aminoglycosides are also nephrotoxic and ototoxic. Although a number of mechanisms have been proposed, it is still unclear how aminoglycosides induce cell death in auditory sensory epithelia and subsequent deafness.

Intra-cochlear trafficking of aminoglycosides.

Cochlear sensory hair cells are pharmacologically sensitive to aminoglycoside antibiotics that are used for treating life-threatening bacterial sepsis. Cochlear tissues are compartmentalized behind an impermeable paracellular barrier called the blood-labyrinth barrier (BLB). Most macromolecules cannot cross the blood-labyrinth barrier; however, aminoglycosides can cross this barrier into the cochlear fluids and enter hair cells, inducing hair cell death and consequent permanent hearing loss or deafness.

TRPV4 enhances the cellular uptake of aminoglycoside antibiotics.

The cochlea and kidney are susceptible to aminoglycoside-induced toxicity. The non-selective cation channel TRPV4 is expressed in kidney distal tubule cells, and hair cells and the stria vascularis in the inner ear. To determine whether TRPV4 is involved in aminoglycoside trafficking, we generated a murine proximal-tubule cell line (KPT2) and a distal-tubule cell line (KDT3).

Frizzled-9 is activated by Wnt-2 and functions in Wnt/beta -catenin signaling.

Frizzled has been known to function as a Wnt receptor. Although there have been a number of mammalian Frizzled members identified, their binding specificities with Wnt and functions in mammalian cells have been poorly understood. Here, we demonstrate that rat Frizzled-9 (Rfz9) functions in Wnt/beta-catenin signaling in 293T cells.