Serotonin receptors: guardians of stable breathing

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Abstract

Disturbances of breathing arising from failures of the respiratory center are not uncommon. Among them, breath holding and apnea occur most frequently as consequences of pulmonary and cardiac diseases, hypoxia, head trauma, cerebral inflammatory processes, genetic defects, degenerative brain diseases, alcoholism, deep anesthesia and drug overdose. They are often life-threatening and fail to respond to existing pharmacotherapies. After extensive research, there is now a reliable basis for new strategies to treat respiratory disturbances by pharmacological manipulation of intracellular signaling pathways, particularly those involving the serotonin receptor family. Specific activation of these pathways effectively prevails respiratory disturbances and can be extended to treatment of life-threatening respiratory disorders in patients.

Section snippets

Serotonin receptors

Serotonin [5-hydroxytryptamine (5-HT)] is an important neurotransmitter that has a key role in controlling a large variety of sensory and motor functions. Serotonergic axons originating from the caudal raphe nuclei in the ventral parts of the brainstem project to all regions of the brain and spinal cord, including the lower brainstem and the pons, where essential elements for the respiratory network are located 22, 23, 24. The raphe system is tonically active and this activity can be modulated

Concluding remarks

In conclusion, recent knowledge about the role of 5-HT receptors in the regulation of breathing, together with an increased understanding of the molecular mechanisms of serotonergic signaling, open an intriguing possibility of treating various respiratory disturbances with drugs directed to the defined 5-HT receptor subtypes. In essence, such a straight-forward therapeutic targeting of convergent intracellular signaling pathways by means of a receptor-specific pharmacology might open novel

Glossary

Glossary

Apneusis:
an abnormal respiratory pattern consisting of a pause at inspiration and prolonged breath holding; a prolonged inspiratory cramp.
Central apnea:
cessation of breathing owing to lack of inspiratory movements; failure of the respiratory network in the brainstem.
Tachypnea:
abnormally fast rate of breathing that is not caused by disturbances of the acid–base balance; leads to metabolically induced hyperpnea such as after exercise.

References (75)

  • D.W. Richter

    Intracellular signal pathways controlling respiratory neurons

    Respir. Physiol.

    (1997)
  • R.H. McAllister-Williams et al.

    The modulation of calcium channel currents recorded from adult rat dorsal raphe neurones by 5-HT1A receptor or direct G-protein activation

    Neuropharmacology

    (1995)
  • F. Artigas

    Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists

    Trends Neurosci.

    (1996)
  • J. Champagnat

    Catecholaminergic depressant effects on bulbar respiratory mechanisms

    Brain Res.

    (1979)
  • P.M. Lalley

    Serotonin 1A-receptor activation suppresses respiratory apneusis in the cat

    Neurosci. Lett.

    (1994)
  • E.G. Ponimaskin

    5-Hydroxytryptamine 4(a) receptor is coupled to the Gα subunit of heterotrimeric G13 protein

    J. Biol. Chem.

    (2002)
  • J. Niu

    Interaction of heterotrimeric G13 protein with an A-kinase-anchoring protein 110 (AKAP110) mediates cAMP-independent PKA activation

    Curr. Biol.

    (2001)
  • F. Lezoualc'h et al.

    The serotonin 5-HT4 receptor and the amyloid precursor protein processing

    Exp. Gerontol.

    (2003)
  • P. Vanhoenacker

    5-HT7 receptors: current knowledge and future prospects

    Trends Pharmacol. Sci.

    (2000)
  • L.P. Baker

    Stimulation of type 1 and type 8 Ca2+/calmodulin-sensitive adenylyl cyclases by the Gs-coupled 5-hydroxytryptamine subtype 5-HT7A receptor

    J. Biol. Chem.

    (1998)
  • J.H. Norum

    Ras-dependent ERK activation by the human G(s)-coupled serotonin receptors 5-HT4(b) and 5-HT7(a)

    J. Biol. Chem.

    (2003)
  • M.L. Vizuete

    Expression of 5-HT7 receptor mRNA in rat brain during postnatal development

    Neurosci. Lett.

    (1997)
  • D.E. Heidmann

    Function and distribution of three rat 5-hydroxytryptamine7 (5-HT7) receptor isoforms produced by alternative splicing

    Neuropharmacology

    (1998)
  • T.W. Lovenberg

    A novel adenylyl cyclase-activating serotonin receptor (5-HT7) implicated in the regulation of mammalian circadian rhythms

    Neuron

    (1993)
  • M.J. Duncan

    Comparison of the effects of aging on 5-HT7 and 5-HT1A receptors in discrete regions of the circadian timing system in hamsters

    Brain Res.

    (1999)
  • J.C. Smith

    Pre-Bötzinger complex: a brainstem region that may generate respiratory rhythm in mammals

    Science

    (1991)
  • H. Onimaru et al.

    A novel functional neuron group for respiratory rhythm generation in the ventral medulla

    J. Neurosci.

    (2003)
  • D.W. Richter

    Generation and maintenance of the respiratory rhythm

    J. Exp. Biol.

    (1982)
  • S.W. Schwarzacher

    Pre-Botzinger complex in the cat

    J. Neurophysiol.

    (1995)
  • D.W. Richter

    Neural Regulation of Respiration: Rhythmogenesis and Afferent Control

    (1996)
  • D.W. Richter

    Voltage-clamp analysis of neurons within deep layers of the brain

    J. Neurosci. Methods

    (1996)
  • D. Büsselberg

    Reorganization of respiratory network activity after loss of glycinergic inhibition

    Pflugers Arch.

    (2001)
  • Feldman, J.L. et al. Breathing: rhythmicity, plasticity, chemosensitivity. Annu. Rev. Neurosci. (in...
  • Büsselberg, D. et al. A combined blockade of glycine and calcium-dependent potassium channels abolishes the repiratory...
  • D.W. Richter

    Neurotransmitters and neuromodulators controlling the hypoxic respiratory response in anaesthetized cats

    J. Physiol.

    (1999)
  • L. Kubin

    Control of upper airway motoneurons during REM sleep

    News Physiol. Sci.

    (1998)
  • E. Lugaresi

    Sleep-related respiratory disorders

    Ital. J. Neurol. Sci.

    (1985)
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