ArticleProceedings of the National Academy of Sciences of the United States of America2020
Isoform-specific regulation of HCN4 channels by a family of endoplasmic reticulum proteins.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 26 citations in OpenAlex.
- SPI1 exacerbates neurogenic bladder dysfunction by enhancing NRSF-mediated suppression of HCN1 and inducing endoplasmic reticulum stress.In vitro cellular & developmental biology. Animal · 2026Article
- Lipid bilayers determine allostery but not intrinsic affinity of cAMP to pacemaker channels.Nature communications · 2026Article
- The proximal N-terminus of IRAG is required for potentiation of HCN4 channels.bioRxiv : the preprint server for biology · 2026Article
- A comprehensive review of HCN channel expression and IJournal of neurophysiology · 2025Review
- Identification of KCNE6, a new member of the KCNE family of potassium channel auxiliary subunits.Communications biology · 2024Article
- LRMP inhibits cAMP potentiation of HCN4 channels by disrupting intramolecular signal transduction.eLife · 2024Article
- Reply to Benndorff and DiFrancesco: Reliable human HCN4 single-channel recordings using the cell-attached configuration in expression systems.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Phosphodiesterase in heart and vessels: from physiology to diseases.Physiological reviews · 2024Review
- A high affinity switch for cAMP in the HCN pacemaker channels.Nature communications · 2024Article
- LRMP inhibits cAMP potentiation of HCN4 channels by disrupting intramolecular signal transduction.bioRxiv : the preprint server for biology · 2024Article
- A gain-of-function HCN4 mutant in the HCN domain is responsible for inappropriate sinus tachycardia in a Spanish family.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Novel Functional Features of cGMP Substrate Proteins IRAG1 and IRAG2.International journal of molecular sciences · 2023Review
- Function of IRAG2 Is Modulated by NO/cGMP in Murine Platelets.International journal of molecular sciences · 2022Article
- Jaw1/LRMP increases CaScientific reports · 2022Article
- Altered cyclic nucleotide binding and pore opening in a diseased human HCN4 channel.Biophysical journal · 2022Article
- Regulation of HCN Channels by Protein Interactions.Frontiers in physiology · 2022Review
- IRAG2 Interacts with IPInternational journal of molecular sciences · 2021Article
- Article
- Bidirectional flow of the funny current (IProceedings of the National Academy of Sciences of the United States of America · 2021Article
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
Ion channels in excitable cells function in macromolecular complexes in which auxiliary proteins modulate 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.