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Roles of GRK Dysfunction in Alzheimer’s Pathogenesis

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G Protein-Coupled Receptor Kinases

Part of the book series: Methods in Pharmacology and Toxicology ((MIPT))

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Abstract

G protein-coupled receptors (GPCRs) mediate a wide variety of physiological functions. GPCR signaling, once activated, is subsequently dampened by receptor desensitization, a procedure initiated by a group of kinases, including GPCR kinases (GRKs). GRK2 upregulation and GRK5 deficiency were reported to occur in Alzheimer’s disease. GRK2 accumulation was proposed to participate in cerebral vascular pathology, whereas GRK5 deficiency is believed to mediate the Alzheimer’s cholinergic neuronal dysfunction and degeneration via the impaired M2/M4 muscarinic receptor desensitization. The GRK dysfunction can be experimentally caused by ß-amyloid, while the subsequent cerebral vascular dysfunction and cholinergic deficiency in turn may worsen the ß-amyloidogenesis. Therefore, the GRK dysfunction appears to link the ß-amyloid accumulation to the cerebrovascular degeneration and the cholinergic degeneration in Alzheimer’s disease. Given that the ß-amyloid hypothesis, the cholinergic hypothesis, and the cerebrovascular hypothesis are all important mainstream hypotheses that are actively pursued to explain the Alzheimer’s pathogenesis, further exploration of their relations may reveal therapeutic strategies that can break their pathogenic links.

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Acknowledgment

This work was supported by grants to W.Z.S. from the Medical Research and Development Service, Department of Veterans Affairs, the Alzheimer’s Association, and resources from the Midwest Biomedical Research Foundation.

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Authors and Affiliations

  1. Laboratory for Alzheimer’s Disease & Aging Research, Veterans Affairs Medical Center, 4801 Linwood Blvd., Kansas City, MO, 64128, USA

    William Z. Suo

  2. Department of Neurology, University of Kansas Medical Center, Kansas City, KS, 66170, USA

    William Z. Suo

  3. Department of Molecular & Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, 66170, USA

    William Z. Suo

  4. The University of Kansas Alzheimer’s Disease Center, Kansas City, KS, 66160, USA

    William Z. Suo

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  1. William Z. Suo
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Correspondence to William Z. Suo .

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Editors and Affiliations

  1. Department of Pharmacology, Vanderbilt University , NASHVILLE, Tennessee, USA

    Vsevolod V. Gurevich

  2. Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA

    Eugenia V. Gurevich

  3. Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA

    John J.G. Tesmer

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Suo, W.Z. (2016). Roles of GRK Dysfunction in Alzheimer’s Pathogenesis. In: Gurevich, V., Gurevich, E., Tesmer, J. (eds) G Protein-Coupled Receptor Kinases. Methods in Pharmacology and Toxicology. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3798-1_10

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  • DOI: https://doi.org/10.1007/978-1-4939-3798-1_10

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