Isoform-specific regulation of HCN4 channels by a family of endoplasmic reticulum proteins

Ion channels in excitable cells function in macromolecular complexes in which auxiliary proteinsmodulate the biophysical properties of the pore-forming subunits. Hyperpolarization-activated, cyclic nucleotide-sensitive HCN4 channels are critical determinants of membrane excitability in cells through...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 30; pp. 18079 - 18090
Main Authors:	Peters, Colin H., Myers, Mallory E., Juchno, Julie, Haimbaugh, Charlie, Bichraoui, Hicham, Du, Yanmei, Bankston, John R., Walker, Lori A., Proenza, Catherine
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 28-07-2020
Subjects:	Animals Binding Biological Sciences Cell Line CHO Cells Cricetulus Cyclic AMP Cyclic AMP - metabolism Dependence Depolarization Electric potential Endoplasmic reticulum Endoplasmic Reticulum - metabolism Excitability Gene Expression Regulation Guanylate kinase Homology Humans Hyperpolarization Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - chemistry Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - genetics Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - metabolism Inositol 1,4,5-trisphosphate receptors Ion channels Ion channels (cyclic nucleotide-gated) Kinases Macromolecules Male Membrane Potentials - drug effects Membrane proteins Membrane Proteins - genetics Membrane Proteins - metabolism Membranes Mice Models, Biological Mouse devices Multigene Family Myocytes, Cardiac - metabolism Nucleotides Pacemakers Phosphoproteins - metabolism Pore formation Potassium Protein Binding Protein Interaction Domains and Motifs Protein Isoforms Proteins Sinoatrial Node - physiology Sinoatrial Node - physiopathology Substrates Surgical implants Thalamus Voltage sinoatrial node LRMP HCN channel ion channel IRAG
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Summary:	Ion channels in excitable cells function in macromolecular complexes in which auxiliary proteinsmodulate the biophysical properties of the pore-forming subunits. Hyperpolarization-activated, cyclic nucleotide-sensitive HCN4 channels are critical determinants of membrane excitability in cells throughout the body, including thalamocortical neurons and cardiac pacemaker cells. We previously showed that the properties of HCN4 channels differ dramatically in different cell types, possibly due to the endogenous expression of auxiliary proteins. Here, we report the discovery of a family of endoplasmic reticulum (ER) transmembrane proteins that associate with and modulate HCN4. Lymphoid-restricted membrane protein (LRMP, Jaw1) and inositol trisphosphate receptor-associated guanylate kinase substrate (IRAG, Mrvi1, and Jaw1L) are homologous proteins with small ER luminal domains and large cytoplasmic domains. Despite their homology, LRMP and IRAG have distinct effects on HCN4. LRMP is a loss-of-function modulator that inhibits the canonical depolarizing shift in the voltage dependence of HCN4 in response to the binding of cAMP. In contrast, IRAG causes a gain of HCN4 function by depolarizing the basal voltage dependence in the absence of cAMP. The mechanisms of action of LRMP and IRAG are independent of trafficking and cAMP binding, and they are specific to the HCN4 isoform. We also found that IRAG is highly expressed in the mouse sinoatrial node where computer modeling predicts that its presence increases HCN4 current. Our results suggest important roles for LRMP and IRAG in the regulation of cellular excitability, as tools for advancing mechanistic understanding of HCN4 channel function, and as possible scaffolds for coordination of signaling pathways.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by Bruce P. Bean, Harvard Medical School, Boston, MA, and approved June 5, 2020 (received for review April 13, 2020) Author contributions: C.H.P., J.J., H.B., J.R.B., L.A.W., and C.P. designed research; C.H.P., M.E.M., J.J., C.H., H.B., Y.D., and L.A.W. performed research; C.H.P., M.E.M., J.J., C.H., H.B., J.R.B., and C.P. analyzed data; and C.H.P. and C.P. wrote the paper.
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.2006238117