A Rare Mutation of β1-Adrenergic Receptor Affects Sleep/Wake Behaviors

Guangsen Shi; Lijuan Xing; David Wu; Bula J Bhattacharyya; Christopher R Jones; Thomas McMahon; S Y Christin Chong; Jason A Chen; Giovanni Coppola; Daniel Geschwind; Andrew Krystal; Louis J Ptáček; Ying-Hui Fu

doi:10.1016/j.neuron.2019.07.026

A Rare Mutation of β₁-Adrenergic Receptor Affects Sleep/Wake Behaviors

Neuron. 2019 Sep 25;103(6):1044-1055.e7. doi: 10.1016/j.neuron.2019.07.026. Epub 2019 Aug 28.

Affiliations

¹ Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
² Department of Neurology, University of Utah, Salt Lake City, UT 84108, USA.
³ Department of Neurology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵ Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: ljp@ucsf.edu.
⁶ Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: ying-hui.fu@ucsf.edu.

Abstract

Sleep is crucial for our survival, and many diseases are linked to long-term poor sleep quality. Before we can use sleep to enhance our health and performance and alleviate diseases associated with poor sleep, a greater understanding of sleep regulation is necessary. We have identified a mutation in the β₁-adrenergic receptor gene in humans who require fewer hours of sleep than most. In vitro, this mutation leads to decreased protein stability and dampened signaling in response to agonist treatment. In vivo, the mice carrying the same mutation demonstrated short sleep behavior. We found that this receptor is highly expressed in the dorsal pons and that these ADRB1⁺ neurons are active during rapid eye movement (REM) sleep and wakefulness. Activating these neurons can lead to wakefulness, and the activity of these neurons is affected by the mutation. These results highlight the important role of β₁-adrenergic receptors in sleep/wake regulation.

Keywords: ADRB1; dorsal pons; familial natural short sleep; sleep duration.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Gene Knock-In Techniques
Humans
Mice
Mutation
Neurons / metabolism
Pedigree
Pontine Tegmentum / cytology
Pontine Tegmentum / metabolism
Receptors, Adrenergic, beta-1 / genetics*
Sleep / genetics*
Sleep Wake Disorders / genetics
Sleep, REM / genetics
Wakefulness / genetics*

Substances

ADRB1 protein, human
Adrb1 protein, mouse
Receptors, Adrenergic, beta-1