Thursday, November 21, 2024
11/21/2024
SUMMARY Developmental and epileptic encephalopathy associated with KCNQ2 channels has been primarily linked to loss-of-function KCNQ2 mutations. However, an increasing number of recurrent KCNQ2 gain-of-function variants (i.e., R201C) have been identified. Patients with the KCNQ2R201C mutation display severe myoclonus and early profound hypoventilation due to reduced chemoreflex. Currently, mechanisms by which KCNQ2 channels control the drive to breathe are unclear. The retrotrapezoid nucleus (RTN) is an important respiratory center; neurons in this region function as respiratory chemoreceptors by regulating breathing in response to changes in tissue CO2. Chemosensitive RTN neurons are activated by an increase in CO2/H+, whereas a gain- of-function Kcnq2 mutation might hyperpolarize RTN neurons and make it more difficult to respond to CO2/H+. Indeed, work from the parent grant showed that expression of the recurrent Kcnq2 mutation Kcnq2R201C in RTN neurons blunted the ventilatory response to CO2. Excitingly, we also found that Kcnq2 channel activity in RTN neurons is regulated by a H+-myo-inositol cotransporter (HMIT) which imports myo-inositol to support production of phosphatidylinositol 4,5-bisphosphate (PIP2), an allosteric activator of Kcnq2 channels. HMIT expression in the RTN region is restricted only to chemosensitive neurons. Therefore, we hypothesize that HMIT is required for Kcnq2 channel activity in RTN neurons. In particular, we propose that H+-dependent myo- inositol transport into RTN neurons by HMIT will increase PIP2 levels and activate Kcnq2 channels to limit CO2/H+-stimulated activity, as well as to maintain neural modulation by neurotransmitters that signal through Gq-coupled receptors and PIP2 hydrolysis. Thus, the objective of this application is to determine the extent to which Kcnq2 channels and HMIT interact to control RTN chemoreception under normal conditions and whether HMIT can be targeted to improve breathing in mice that express Kcnq2R201C. The three Specific Aims of this project are: 1) determine the extent to which HMIT influences Kcnq2 channel regulation of chemosensitive RTN neurons; 2) determine contributions of Kcnq2 channels and HMIT interactions to RTN chemoreceptor network excitability; and 3) to establish HMIT in RTN neurons as a therapeutic target for Kcnq2 associated breathing abnormalities. The rationale for this research is that by understanding how HMIT regulates Kcnq2 channel activity in RTN neurons, we can lay a foundation for developing treatments for respiratory problems associated with Kcnq2 mutations.
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