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Differential Glycosylation of the Inwardly Rectifying Potassium Channel Kir7.1 by G protein-coupled Receptors

dc.creatorCarrington, Sheridan Jared S
dc.description.abstractKir7.1 is an inwardly rectifying potassium channel with important roles in the regulation of the membrane potential in retinal pigment epithelium, uterine smooth muscle, and hypothalamic neurons. Regulation of G protein–coupled inwardly rectifying potassium (GIRK) channels by G protein–coupled receptors (GPCRs) via the G protein beta gamma subunits has been well characterized. However, how Kir channels are regulated is incompletely understood. We report here that Kir7.1 is also regulated by GPCRs, but through a different mechanism. Using Western blot analysis, we observed that multiple GPCRs tested caused a striking reduction in the complex glycosylation of Kir7.1. Further, GPCR-mediated reduction of Kir7.1 glycosylation in HEK293T cells did not alter its expression at the cell surface but decreased channel activity. Of note, mutagenesis of the sole Kir7.1 glycosylation site reduced conductance and open probability, as indicated by single-channel recording. Additionally, we report that the L241P mutation of Kir7.1 associated with Lebers congenital amaurosis (LCA), an inherited retinal degenerative disease has significantly reduced complex glycosylation. Collectively, these results suggest that Kir7.1 channel glycosylation is essential for function, and this activity within cells is suppressed by most GPCRs. The Melanocortin 4 receptor (MC4R), a GPCR previously reported to induce ligand-regulated activity of this channel, is the only GPCR tested that does not have this effect on Kir7.1.
dc.subjection channel
dc.subjection channel
dc.subjectpotassium channel
dc.titleDifferential Glycosylation of the Inwardly Rectifying Potassium Channel Kir7.1 by G protein-coupled Receptors
dc.contributor.committeeMemberJerod S. Denton, Ph.D.
dc.contributor.committeeMemberHeidi E. Hamm, Ph.D.
dc.contributor.committeeMemberAnne K. Kenworthy, Ph.D.
dc.contributor.committeeMemberDavid A. Jacobson, Ph.D.
dc.contributor.committeeMemberAdvisor: Roger D. Cone, Ph.D.
dc.type.materialtext Physiology and Biophysics University
dc.contributor.committeeChairRoger J. Colbran, Ph.D.

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