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

Peters, Colin H.; Myers, Mallory E.; Juchno, Julie; Haimbaugh, Charlie; Bichraoui, Hicham; Du, Yanmei; Bankston, John R.; Walker, Lori A.; Proenza, Catherine

doi:10.1101/2020.04.10.022483

Cited by 2 publications

(2 citation statements)

References 71 publications

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“…HEK Cell Electrophysiology. HEK 293 cells stably expressing HCN4 (generously provided by Martin Biel's laboratory, Ludwig-Maximilians-Universität, Munich, Germany) were grown as previously described (83). Recordings were performed in the whole-cell configuration in recording Tyrode's extracellular solution with pipettes filled with a K-aspartate intracellular solution containing 0 or 1 mM cAMP as indicated.…”

Section: Methodsmentioning

confidence: 99%

Bidirectional flow of the funny current (I _f ) during the pacemaking cycle in murine sinoatrial node myocytes

Peters

Liu

Morotti

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Sinoatrial node myocytes (SAMs) act as cardiac pacemaker cells by firing spontaneous action potentials (APs) that initiate each heartbeat. The funny current (If) is critical for the generation of these spontaneous APs; however, its precise role during the pacemaking cycle remains unresolved. Here, we used the AP-clamp technique to quantify If during the cardiac cycle in mouse SAMs. We found that If is persistently active throughout the sinoatrial AP, with surprisingly little voltage-dependent gating. As a consequence, it carries both inward and outward current around its reversal potential of −30 mV. Despite operating at only 2 to 5% of its maximal conductance, If carries a substantial fraction of both depolarizing and repolarizing net charge movement during the firing cycle. We also show that β-adrenergic receptor stimulation increases the percentage of net depolarizing charge moved by If, consistent with a contribution of If to the fight-or-flight increase in heart rate. These properties were confirmed by heterologously expressed HCN4 channels and by mathematical models of If. Modeling further suggested that the slow rates of activation and deactivation of the HCN4 isoform underlie the persistent activity of If during the sinoatrial AP. These results establish a new conceptual framework for the role of If in pacemaking, in which it operates at a very small fraction of maximal activation but nevertheless drives membrane potential oscillations in SAMs by providing substantial driving force in both inward and outward directions.

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Section: Methodsmentioning

confidence: 99%

Bidirectional flow of the funny current (I _f ) during the pacemaking cycle in murine sinoatrial node myocytes

Peters

Liu

Morotti

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…To uncover how Jaw1 affects Ca 2+ dynamics upon physiological stimulation, we created HEK293 Flp-In T-REx Jaw1 inducible-expressed cells with doxycycline (Dox) treatment-inducible Jaw1 expression. As previously reported, endogenous Jaw1 is expressed in HEK293 cells at a low level [21]. First, we generated HEK293 Flp-In T-REx Jaw1 KO cells (Jaw1 KO cells) by CRISPR/Cas9 (see Supplementary Fig.…”

Section: Jaw1 Increases the Ca 2+ In Ux In An Expression Leveldepende...mentioning

confidence: 99%

Jaw1/LRMP increases Ca2+ influx upon GPCR stimulation with heterogeneous effect on the activity of each ITPR subtype

Nishikawa

Okumura

Kozono

et al. 2022

Preprint

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Ca2+ influx upon G protein-coupled receptor (GPCR) stimulation is observed as a cytosolic Ca2+ concentration oscillation crucial to initiating downstream responses including cell proliferation, differentiation, and cell-cell communication. Although Jaw1 is known to interact with inositol 1,4,5-triphosphate receptor (ITPRs), Ca2+ channels on the endoplasmic reticulum, the function of Jaw1 in the Ca2+ dynamics with physiological stimulation remains unclear. In this study, using inducible Jaw1-expressing HEK293 cells, we showed that Jaw1 increases Ca2+ influx by GPCR stimulation via changing the Ca2+ influx oscillation pattern. Furthermore, we showed that Jaw1 increases the Ca2+ release activity of all ITPR subtypes in a subtly different manner. It is well known that the Ca2+ influx oscillation pattern varies from cell type to cell type, therefore these findings provide an insight into the relationship between the heterogeneous Ca2+ dynamics and the specific ITPR and Jaw1 expression patterns.

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

Cited by 2 publications

References 71 publications

Bidirectional flow of the funny current (I _f ) during the pacemaking cycle in murine sinoatrial node myocytes

Bidirectional flow of the funny current (I _f ) during the pacemaking cycle in murine sinoatrial node myocytes

Jaw1/LRMP increases Ca2+ influx upon GPCR stimulation with heterogeneous effect on the activity of each ITPR subtype

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

Cited by 2 publications

References 71 publications

Bidirectional flow of the funny current (I f ) during the pacemaking cycle in murine sinoatrial node myocytes

Bidirectional flow of the funny current (I f ) during the pacemaking cycle in murine sinoatrial node myocytes

Jaw1/LRMP increases Ca2+ influx upon GPCR stimulation with heterogeneous effect on the activity of each ITPR subtype

Contact Info

Product

Resources

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Bidirectional flow of the funny current (I _f ) during the pacemaking cycle in murine sinoatrial node myocytes

Bidirectional flow of the funny current (I _f ) during the pacemaking cycle in murine sinoatrial node myocytes