NIH Reporter #11415742

Cellular/Molecular Mechanisms of Respiratory Neuronal Chemosensitivity

This NIH grant supports research to identify and understand the cellular and molecular mechanisms of respiratory neuronal chemosensitivity, focusing on CO2/H+ sensing neurons in the brainstem and their role in respiratory control and adaptation.

Description

An interoceptive system within the CNS monitors levels of CO2 (or its proxy, H+) and regulates respiratory drive for rapid homeostatic control of blood gases and systemic acid-base balance; dysfunction of this central respiratory chemoreception is cause or consequence of numerous hypoventilation syndromes. Despite recognition of this chemoreflex system since the early 1900s, and its importance for understanding respiratory (patho)physiology, the identity of the relevant sensory element(s) remains a point of significant controversy largely because none of the candidate cellular sensors and molecular detectors have yet fulfilled the requisite experimental criteria. Moreover, the molecular basis for CO2/H+ sensing, and how those are established developmentally and adapted to pathological conditions, remain matters of continuing scrutiny. Compelling evidence implicates a discrete group of developmentally specified and phenotypically characterized neurons located in the brainstem retrotrapezoid nucleus (RTN) as respiratory chemosensors, and suggests that CO2/H+ detection by RTN neurons is mediated by a pH sensitive G protein-coupled receptor (GPR4) and background K+ channel (TASK-2). However, the evidentiary record remains incomplete.

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