Nociception is the process whereby primary afferent somatosensory neurons recognize and respond to noxious stimuli. In addition to initiating acute pain responses, nociceptor activation can produce local inflammation leading to pain hypersensitivity. Tissue acidosis (i.e. reduction in local pH) is an important hallmark of this response, and is associated with a range of physiological insults, such as infection, ischemia, tumor growth, and arthritis. Indeed, extracellular protons enhance excitability of primary afferent nociceptors, thereby producing acute pain and/or pain hypersensitivity. Members of the acid sensing ion channel (ASIC) family are believed to play important roles in nociception and pain by functioning as sensors for extracellular protons. For example, the ASIC3 subtype likely accounts for ischemic pain associated with large, rapidly inactivating proton-evoked currents in neurons that innervate skeletal or cardiac muscle. However, additional roles for ASIC channels in nociception have remained enigmatic for a variety of reasons. First, a dearth of pharmacological tools has made it difficult to manipulate these channels in vivo. Second, mice lacking specific ASIC channel subtypes have failed to revealed clear or robust phenotypes in regard to acid-evoked pain or other aspects of nociception. Third, a comprehensive analysis of ASIC channel expression and localization - which is critical to deciphering physiological roles for these channels in nociception and pain - remains incomplete. Finally, some ASIC subtypes (e.g. ASIC2a) respond only to extreme extracellular acidosis (pH <5), suggesting the existence of other endogenous modulators for these channels that may be produced under pathophysiological conditions of tissue injury and/or chronic inflammation. The goal of this proposal is to address these and other questions by applying genetic, physiologic, and biochemical methods to develop a comprehensive view of ASIC subtype function, pharmacology, and expression in the somatosensory system.
The specific aims are to (i) develop a comprehensive map of ASIC channel expression using gene targeted reporter mice to visualize ASIC-positive nerve fibers with exquisite sensitivity and fidelity;(ii) characterize functional properties of ASIC-expressing sensory neurons and nerve fibers from these genetically-labeled mice using a range of electrophysiological and live-cell imaging methods;(iii) screen for novel endogenous ASIC modulators in extracts of normal and injured tissues using a range of biochemical, functional, and behavioral assays. Together, these aims will address important unresolved questions concerning ASIC function as key steps toward the rational development of novel therapeutic agents that target a range of chronic inflammatory pain syndromes.

Public Health Relevance

This project investigates a family of membrane ion channels that detect tissue acidosis and activate nerve fibers that generate pain signals. Results from these studies will expand our understanding of an important class of ion channels that contribute to pain sensation, thereby illuminating therapeutic strategies (such as novel drugs) for treating chronic pain syndromes associated with arthritis, inflammatory bowel disease, cancer, and other forms of tissue and nerve injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS081115-03
Application #
8661323
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Chen, Daofen
Project Start
2012-09-01
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
$367,259
Indirect Cost
$129,559
Name
University of California San Francisco
Department
Physiology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Baconguis, Isabelle; Bohlen, Christopher J; Goehring, April et al. (2014) X-ray structure of acid-sensing ion channel 1-snake toxin complex reveals open state of a Na(+)-selective channel. Cell 156:717-29