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KATP channels confer survival advantage in cocaine overdose

Molecular Psychiatry volume 12, pages 1060–1061 (2007)Cite this article

Cocaine use affects more than 30 million people in this country, and is responsible for the majority of deaths ascribed to drug overdose.1 While the pharmacodynamics of cocaine toxicity are increasingly understood, the molecular determinants that define fatal outcome remain largely unknown. Indeed, in cocaine poisoning the mainstay of management is supportive, limited predominantly to sedation and monitoring of vital signs.2 Here, we report that the susceptibility to cocaine-induced mortality is genetically controlled. By identifying the KCNJ11 gene as a safeguard element in the response to cocaine overdose, the present study unmasks a previously unrecognized framework for targeted therapy of cocaine intoxication.

An overdriven activation of the sympathetic nervous system, which results in a mismatch of demand and supply producing seizures, heart rhythm disorders and cardiopulmonary collapse, is an established substrate of cocaine toxicity.3 By inhibiting reuptake of catecholamines in presynaptic neurons, cocaine induces an excessive accumulation of sympathetic neurotransmitters, resulting in a general state of hyperadrenergic stimulation.4 Distributed throughout the body, ATP-sensitive K+ (KATP) channels have been recently implicated in securing tolerance to systemic stress imposed by a sympathetic surge.5 KATP channels operate as unique molecular rheostats, capable of adjusting membrane potential-dependent functions to match cellular metabolic demands.6 Underscoring the critical role for KATP channels in vital homeostatic functions, targeted disruption of KCNJ11, the gene encoding the pore-forming Kir6.2 subunit of KATP channels, precipitates generalized seizure,7 heart failure8 and arrhythmia under stress.9 Therefore, we tested here whether KATP channel function provides a protective mechanism in the setting of cocaine toxicity.

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Acknowledgements

This work was supported by grants from the National Institutes of Health, Marriott Heart Disease Research Program, Marriott Foundation, Ted Nash Long Life Foundation and Japanese Ministry of Education, Science, Sports, Culture and Technology.

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Authors and Affiliations

  1. Division of Cardiovascular Diseases, Department of Internal Medicine, Marriott Heart Disease Research Program, Mayo Clinic, Rochester, MN, USA

    S Reyes, G C Kane & A Terzic

  2. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA

    S Reyes, G C Kane & A Terzic

  3. Department of Medical Genetics, Mayo Clinic, Rochester, MN, USA

    S Reyes, G C Kane & A Terzic

  4. Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

    T Miki & S Seino

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  1. S Reyes
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  2. G C Kane
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  3. T Miki
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  4. S Seino
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  5. A Terzic
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Correspondence to A Terzic.

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The authors declared that they have no competing interests.

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Reyes, S., Kane, G., Miki, T. et al. KATP channels confer survival advantage in cocaine overdose. Mol Psychiatry 12, 1060–1061 (2007). https://doi.org/10.1038/sj.mp.4002083

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