Research Areas
Functional roles of serotonin 2C receptor (5HT2C) isoforms.
The 2C-subtype of serotonin 2C receptor (5HT2C) is a member of the G-protein coupled receptor superfamily which is expressed in many brain regions and plays an important role in regulating appetite, metabolism, mood, and sleep. Transcripts encoding the 5HT2C receptor undergo up to five adenosine-to-inosine (A-to-I) RNA editing events to generate as many as 24 protein isoforms with unique signaling properties. Our research focuses on examining the differential expression and function of these edited 5HT2C isoforms, as well as clinical implications resulting from the dysregulation of normal 5HT2C editing patterns.
Kv1.1 editing and K+ channel function
The alpha-subunit of the Kv1.1-subtype of voltage-gated potassium channel (Kv) plays an important role in regulating neuronal excitability. By dampening excitability at the axon initial segment and juxtaparanodal region, it can influence action potential initiation, propagation and reduce nerve terminal excitability, permitting fine-tuning of neurotransmitter release. Underscoring its physiological importance, genetic knockout studies have revealed that mice lacking Kv1.1 expression develop spontaneous seizures, hyperalgesia, and neurogenic cardiac dysfunction. RNA transcripts encoding the Kv1.1 subunit are modified by a site-specific A-to-I editing event in which a genomically-encoded isoleucine (ATT) is converted to a valine (ITT) codon to change the identity of amino acid 400 within the protein. This amino acid lies within the S6 transmembrane domain predicted to line the ion-conducting pore of the channel and changes in Kv1.1 editing have been shown to affect the rate of channel recovery from inactivation.
Physiological role(s) of CAPS1 editing
Calcium-dependent activator protein for secretion 1 (CAPS1) serves as a priming factor for vesicular fusion associated with the regulated secretion of peptides, neurotransmitters and hormones from synaptic and dense core vesicles. The RNA encoding CAPS1 undergoes a site-specific adenosine-to-inosine RNA editing event which can alter a genomically-encoded glutamate to a glycine codon within the carboxyl-terminal domain previously shown to be responsible for interactions with large dense-core granules. CAPS1 is prevalent throughout the central nervous system and editing levels in the mouse brain reach 30% in the frontal cortex. We are interested in the physiological role(s) for CAPS1 editing and are currently examining the consequences of editing on the regulation of CAPS1-dependent modulation of synaptic vesicle release and recycling.