title: Gα14 subunit-mediated inhibition of voltage-gated Ca2+ and K+ channels via neurokinin-1 receptors in rat celiac-superior mesenteric ganglion neurons.
abstract: The mechanisms by which G proteins modulate voltage-gated Ca(2+)channel currents (CaV), particularly CaV2.2 and CaV2.3, are voltage dependent (VD) or voltage independent (VI). VD pathways are typically mediated by Gαi/oand GαSsubfamilies. On the other hand, VI inhibition modulation is coupled to the Gαqsubfamily and signaling pathways downstream of phospholipase C stimulation. In most studies, this latter pathway has been shown to be linked to Gαqand/or Gα11protein subunits. However, there are no studies that have examined whether natively expressed Gα14subunits (Gαqsubfamily member) couple G protein-coupled receptors (GPCR) with CaV2.2 channels. We report that Gα14subunits functionally couple the substance P (SP)/neurokinin-1 (NK-1) receptor pathway to CaV2.2 channels in acutely dissociated rat celiac-superior mesenteric ganglion (CSMG) neurons. Exposure of CSMG neurons to SP blocked the CaV2.2 currents in a predominantly VD manner that was pertussis toxin and cholera toxin resistant, as well as Gαq/11independent. However, silencing Gα14subunits significantly attenuated the SP-mediated Ca(2+)current block. In another set of experiments, exposure of CSMG neurons to SP led to the inhibition of KCNQ K(+)M-currents. The SP-mediated M-current block was significantly reduced in neurons transfected with Gα14small-interference RNA. Finally, overexpression of the GTP-bound Gαq/11binding protein RGS2 did not alter the block of M-currents by SP but significantly abolished the oxotremorine methiodide-mediated M-current inhibition. Taken together, these results provide evidence of a new Gα14-coupled signaling pathway that modulates CaV2.2 and M-currents via SP-stimulated NK-1 receptors in CSMG neurons.
authors: Department of Anesthesiology and Perioperative Medicine, Penn State College of Medicine, Hershey, Pennsylvania.
authors: Shigekazu
authors: S
authors: Sugino
authors: Department of Anesthesiology and Perioperative Medicine, Penn State College of Medicine, Hershey, Pennsylvania.
authors: Mohamed
authors: M
authors: Farrag
authors: Department of Anesthesiology and Perioperative Medicine, Penn State College of Medicine, Hershey, Pennsylvania vruizvelasco@psu.edu.
authors: Victor
authors: V
authors: Ruiz-Velasco
mesh_terms: D000200:Action Potentials; D000818:Animals; D020908:Calcium Channels, R-Type / Q000378:metabolism*; D002478:Cells, Cultured; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism*; D005728:Ganglia, Sympathetic / Q000166:cytology / Q000378:metabolism*; D051656:KCNQ Potassium Channels / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D020710:RGS Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D015290:Second Messenger Systems
chemical_list: D020908:Calcium Channels, R-Type; D044385:GTP-Binding Protein alpha Subunits; D051656:KCNQ Potassium Channels; D020710:RGS Proteins; C514563:RGS2 protein, rat; D018040:Receptors, Neurokinin-1
keywords: Ca2+ channel modulation; sympathetic ganglia; whole cell patch clamp