Calcium inhibits the funny current (If)in sinoatrial myocytes

Peters, Colin H.; Peraza, Diego A.; Blecker, Lucas M.; Bankston, John R.; Proenza, Catherine

doi:10.1016/j.bpj.2022.11.2088

“…The cAMP-dependent shift in HCN4 (~14 mV) is smaller than in HCN2 (~20 mV; Table 2 ). Transduction of cAMP binding is sensitive to divalent cations in HCN4 but not HCN2 ( Saponaro et al, 2021 ; Peters et al, 2023 ). And, the cAMP-dependent shift in activation can be disrupted in HCN4 by regulatory factors such as cyclic-dinucleotides ( Lolicato et al, 2014 ) as well as LRMP and IRAG ( Peters et al, 2020 ).…”

Section: Discussionmentioning

confidence: 98%

“…Despite their homology, cAMP signal transduction in HCN4 appears less robust than in HCN2. The cAMP-dependent shift in HCN4 (∼14 mV) is smaller than in HCN2 (∼20 mV; Table 1 ); in HCN4, but not HCN2, the transduction of cAMP is sensitive to divalent cations (Saponaro et al, 2021 ;Peters et al, 2023 ); and cAMP-dependent shifts in activation can be disrupted in HCN4 by regulatory factors such as cyclic-dinucleotides and LRMP (Lolicato et al, 2014 ), It's likely that the difference in orientation of the C-linker relative to the S4-S5 linker accounts for differences in cAMP signal transduction in HCN4 compared to HCN2. Indeed, mutating the non-conserved residues to the corresponding HCN2 amino acids (P545A/T547F) abolishes LRMP regulation of HCN4 (Fig.…”

Section: An Intramolecular Transduction Centre Between the C-linker H...mentioning

confidence: 95%

LRMP inhibits cAMP potentiation of HCN4 channels by disrupting intramolecular signal transduction

Peters,

Singh,

Langley

et al. 2024

eLife

0

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Lymphoid restricted membrane protein (LRMP) is a specific regulator of the hyperpolarization-activated cyclic nucleotide-sensitive isoform 4 (HCN4) channel. LRMP prevents cAMP-dependent potentiation in HCN4 but the interaction domains, mechanisms of action, and basis for isoform-specificity remain unknown. Here we identify the domains of LRMP essential for regulation, we show that LRMP acts by disrupting the intramolecular signal transduction between cyclic nucleotide binding and gating, and we demonstrate that non-conserved regions in HCN4 are required for LRMP isoform-specificity. Using patch clamp electrophysiology and Förster resonance energy transfer (FRET), we show that the initial 227 residues of LRMP and the N-terminus of HCN4 are necessary for LRMP to interact with HCN4. We also found that the HCN4 N-terminus and HCN4-specific residues in the C-linker are necessary for regulation of HCN4 by LRMP. Taken together, these results suggest that LRMP modulates HCN4 through an isoform-specific interaction involving the N-terminals of both proteins, and that this interaction inhibits the transduction between cAMP binding and channel activation via an interface involving the N-terminus, C-linker, and S4-S5 linker of HCN4.

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“…Despite their homology, cAMP signal transduction in HCN4 appears less robust than in HCN2. The cAMP-dependent shift in HCN4 (~14 mV) is smaller than in HCN2 (~20 mV; Table 1); in HCN4, but not HCN2, the transduction of cAMP is sensitive to divalent cations (Saponaro et al, 2021;Peters et al, 2023); and cAMP-dependent shifts in activation can be disrupted in HCN4 by regulatory factors such as cyclic-dinucleotides and LRMP (Lolicato et al, 2014), It's likely that the difference in orientation of the C-linker relative to the S4-S5 linker accounts for differences in cAMP signal transduction in HCN4 compared to HCN2. Indeed, mutating the nonconserved residues to the corresponding HCN2 amino acids (P545A/T547F) abolishes LRMP regulation of HCN4 (Fig.…”

Section: Proposed Model: Lrmp Disrupts Camp Regulation Of Hcn4 Activa...mentioning

confidence: 94%

LRMP inhibits cAMP potentiation of HCN4 channels by disrupting intramolecular signal transduction

Peters,

Singh,

Langley

et al. 2023

Preprint

0

View full text Add to dashboard Cite

Lymphoid restricted membrane protein (LRMP) is a specific regulator of the hyperpolarization-activated cyclic nucleotide-sensitive isoform 4 (HCN4) channel. LRMP prevents cAMP-dependent potentiation in HCN4 but the interaction domains, mechanisms of action, and basis for isoform-specificity remain unknown. Here we identify the domains of LRMP essential for regulation, we show that LRMP acts by disrupting the intramolecular signal transduction between cyclic nucleotide binding and gating, and we demonstrate that non-conserved regions in HCN4 are required for LRMP isoform-specificity. Using patch clamp electrophysiology and Forster resonance energy transfer (FRET), we show that the initial 227 residues of LRMP and the N-terminus of HCN4 are necessary for LRMP to interact with HCN4. We also found that the HCN4 N-terminus and HCN4-specific residues in the C-linker are necessary for regulation of HCN4 by LRMP. Taken together, these results suggest that LRMP modulates HCN4 through an isoform-specific interaction involving the N-terminals of both proteins, and that this interaction inhibits the transduction between cAMP binding and channel activation via an interface involving the N-terminus, C-linker, and S4-S5 linker of HCN4.

show abstract

LRMP inhibits the cAMP-dependence of HCN4 channels by disrupting intramolecular signal transduction

Peters,

Singh,

Langley

et al. 2023

Preprint

0

View full text Add to dashboard Cite

Lymphoid restricted membrane protein (LRMP) is a specific regulator of the hyperpolarization-activated cyclic nucleotide-sensitive isoform 4 (HCN4) channel. LRMP prevents cAMP-dependent potentiation in HCN4 but the interaction domains, mechanisms of action, and basis for isoform-specificity remain unknown. Here we identify the domains of LRMP essential for regulation, we show that LRMP acts by disrupting the intramolecular signal transduction between cyclic nucleotide binding and gating, and we demonstrate that non-conserved regions in HCN4 are required for LRMP isoform-specificity. Using patch clamp electrophysiology and Förster resonance energy transfer (FRET), we show that the initial 227 residues of LRMP and the N-terminus of HCN4 are necessary for LRMP to interact with HCN4. We also found that the HCN4 N-terminus and HCN4-specific residues in the C-linker are necessary for regulation of HCN4 by LRMP. Taken together, these results suggest that LRMP modulates HCN4 through an isoform-specific interaction involving the N-terminals of both proteins, and that this interaction inhibits the transduction between cAMP binding and channel activation via an interface involving the N-terminus, C-linker, and S4-S5 linker of HCN4.

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Calcium inhibits the funny current (If)in sinoatrial myocytes

Cited by 5 publications

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LRMP inhibits cAMP potentiation of HCN4 channels by disrupting intramolecular signal transduction

LRMP inhibits cAMP potentiation of HCN4 channels by disrupting intramolecular signal transduction

LRMP inhibits cAMP potentiation of HCN4 channels by disrupting intramolecular signal transduction

LRMP inhibits the cAMP-dependence of HCN4 channels by disrupting intramolecular signal transduction

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