K(ATP) channel pharmacogenomics: from bench to bedside - PubMed (original) (raw)

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K(ATP) channel pharmacogenomics: from bench to bedside

S Sattiraju et al. Clin Pharmacol Ther. 2008 Feb.

Abstract

Inheritance plays a significant role in defining drug response and toxicity. Advances in molecular pharmacology and modern genomics emphasize genetic variation in dictating inter-individual pharmacokinetics and pharmacodynamics. A case in point is the homeostatic ATP-sensitive potassium (K(ATP)) channel, an established drug target that adjusts membrane excitability to match cellular energetic demand. There is an increased recognition that genetic variability of the K(ATP) channel impacts therapeutic decision-making in human disease.

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Conflict of interest statement

CONFLICT OF INTEREST

The authors declared no conflict of interest.

Figures

Figure 1

Figure 1

KATP channels in the pancreatic β-cell control insulin release. Hyperglycemia translates into increased transport of glucose into β-cells, resulting in elevated intracellular ATP promoting closure of KATP channels and membrane depolarization leading to opening of voltage-gated Ca2 +channels and Ca2+influx, which triggers insulin release. Inactivating KATP channel mutations lead to overactivated insulin release and HHI, whereas activating channel mutations induce membrane hyperpolarization, impairing insulin release and resulting in neonatal diabetes mellitus (NDM).

Figure 2

Figure 2

The KATP channel sensitivity to ATP determines clinical outcome. Genetic variation in KCNJ11 and _ABCC8-_encoded Kir6.2 and SUR1 subunits translates into varying degrees of disease severity correlating with altered sensitivity of the ATP channel. Representative polymorphisms in KCNJ11 and ABCC8 lead to phenotypes that range from transient forms of neonatal diabetes mellitus (NDM) to the more severe developmental delay, epilepsy, and permanent neonatal diabetes (DEND) syndrome.

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