New Modes of GPCR Signalling

ABSTRACT
Acid Sensing Ion Channels: A Novel Therapeutic Target for Anxiety and
Depression?
John Wemmie
University of Iowa Carver College of Medicine, USA
Acid sensing ion channels (ASICs) are members of the degenerin/epithelial sodium
channel family that are activated by low extracellular pH. Several ASIC subunits are
expressed in the brain including ASIC1a, 2a, and 2b. of these, our work suggests that
ASIC1a is critical for acid-evoked currents in brain neurons. Disrupting ASIC1a in
mice eliminated currents in CNS neurons evoked by pH as low as 5.0. Subcellular
localization suggests ASIC1a is distributed to the neuron cell body, dendrites, and
dendritic spines, where it confers pH sensitivity, increases intracellular Ca 2+ , and
promotes synaptic plasticity. ASIC1a protein was found to be particularly abundant in
brain structures that underlie fear, anxiety, and depression-related behaviors, including
the basolateral amygdala. Consistent with these observations, loss of ASIC1a
disrupted fear-related learning and memory. Loss of ASIC1a also reduced
unconditioned fear, anxiety, and depression-related behaviors in mice. Supporting a
role for ASIC1a as a brain pH sensor, we found that ASIC1a in the amygdala mediates
fear and anxiety responses to CO2 inhalation and brain acidosis. This observation that
suggests that ASICs may underlie the well-described ability of CO2 to triggers panic
attacks in panic disorder patients. Together, these findings raise the possibility that
ASIC1a might provide a novel and effective therapeutic target for anxiety disorders and
depression.