How does adrenaline accelerate the heart?

Brown, Hilary F.; DiFrancesco, Dario; Noble, S J

doi:10.1038/280235a0

Cited by 520 publications

(374 citation statements)

References 9 publications

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“…charge ring ͉ fluctuation analysis ͉ single-channel patch clamp ͉ cyclic nucleotide-gated ͉ hyperpolarization-activated cyclic nucleotide-modulated H yperpolarization-activated cyclic nucleotide-modulated (HCN) ion channels, also known as pacemaker channels, are critical components in the production of rhythmic activity in both cardiac and neural cells (1)(2)(3)(4)(5)(6). Similar to other voltagegated cation channels, HCN channels are tetramers.…”

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confidence: 99%

The carboxyl-terminal region of cyclic nucleotide-modulated channels is a gating ring, not a permeation path

Johnson

Zagotta

2005

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

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The recent elucidation of the structure of the carboxyl-terminal region of the hyperpolarization-activated cyclic nucleotide-modulated (HCN2) channel has prompted us to investigate a curious feature of this structure in HCN2 channels and in the related CNGA1 cyclic nucleotide-gated (CNG) channels. The crystallized fragment of the HCN2 channel contains both the cyclic nucleotide-binding domain (CNBD) and the C-linker region, which connects the CNBD to the pore. At the center of the fourfold-symmetric structure is a tunnel that runs perpendicular to the membrane. The narrowest part of the tunnel is Ϸ10 Å in diameter and is lined by a ring of negatively charged amino acids: D487, E488, and D489. Many ion channels have ''charge rings'' that focus permeant ions at the mouth of the pore and increase channel conductance. We used nonstationary fluctuation analysis and single-channel recording, coupled with site-directed mutagenesis and cysteine modification, to determine whether this part of HCN and CNG channels might be an extension of the permeation pathway. Our results indicate that modifying charge-ring amino acids affects gating but not ion permeation in HCN2 and CNG channels. Thus, this portion of the channel is not an obligatory part of the ion path but instead acts as a ''gating ring.'' The carboxyl-terminal region of these channels must hang below the pore much like the ''hanging gondola'' of voltage-gated potassium channels, but the permeation pathway must exit the protein before the level of the ring of charged amino acids.charge ring ͉ fluctuation analysis ͉ single-channel patch clamp ͉ cyclic nucleotide-gated ͉ hyperpolarization-activated cyclic nucleotide-modulated

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mentioning

confidence: 99%

The carboxyl-terminal region of cyclic nucleotide-modulated channels is a gating ring, not a permeation path

Johnson

Zagotta

2005

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

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“…The peptide(s) released from sensory fibers in the atrium was suggested to express a positive chronotropic effect. On the other hand, peptide release was not involved in the effects of isoproterenol and histamine, which promote the positive chronotropic effect through specific receptormediated activation of adenylate cyclase (14). Furthermore, we examined the effects of capsaicin on the rhythmic activity of isolated guinea pig atrium preparations.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the activation of 5-HT3 receptors on the sensory nerve terminals brought about the ruthenium red-sensitive Ca 2+ influx and resulted in the release of CGRP from capsaicin-sensitive stores. CGRP then activates CGRP 1 -type receptors, which are coupled via Gs to the activation of adenylate cyclase and increase the pacemaker current (If) (14). The If has been reported to be modulated by ligand-dependent channels (modulated by cAMP) as well as by voltage-gated channels (activation by hyperpolarization) (20).…”

Section: Discussionmentioning

confidence: 99%

5-HT-Induced, 5-HT3 Receptor-Mediated, and Ruthenium Red-and Capsaicin-Sensitive Positive Chronotropic Effects in the Isolated Guinea Pig Atrium

Nishio

Morimoto

Hisaoka

et al. 2002

Japanese Journal of Pharmacology

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ABSTRACT-We investigated the mechanisms of 5-HT-induced tachycardia, which we reported previously to be triggered by 5-HT3 receptor stimulation, in the isolated guinea pig atrium in comparison with that induced by isoproterenol and histamine. We found that 5-HT-induced tachycardia was completely inhibited by ruthenium red. 5-HT-induced tachycardia was reduced in the capsaicin pre-treated atrium as well as in the presence of capsaicin. The effects of isoproterenol and histamine were not affected by ruthenium red or capsaicin treatment. Furthermore, 5-HT-induced tachycardia was found to be potentiated by thiorphan, an inhibitor of peptide degeneration. Calcitonin gene-related peptide (CGRP) (1 -37), a full agonist of CGRP 1 -like receptors, was found to act selectively as a potent stimulator of chronotropic action. CGRP (8 -37), an antagonist of CGRP 1 -type receptors, inhibited 5-HT-induced tachycardia as well as effects induced by CGRP (1 -37). The observation that tetrodotoxin failed to affect 5-HT-induced tachycardia excluded the involvement of 5-hydroxytryptaminergic interneurons. Thus, we confirmed that the mechanism of 5-HTinduced tachycardia is distinct from that induced by isoproterenol and histamine. In conclusion, the activation of 5-HT 3 receptors on the sensory nerve terminals brought about ruthenium red-sensitive Ca 2+ influx and resulted in the release of CGRP from capsaicin-sensitive stores, and then CGRP stimulated CGRP 1 -like receptors to produce 5-HT-induced tachycardia.

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“…HCN currents can be identified based on their slow activation by hyperpolarizing voltage steps and selective blockade by ZD7288. Sensitivity to cAMP makes I h currents susceptible to modulation by GPCRs, perhaps most famously exemplified by the effect of adrenaline acting though Β-adrenergic receptors and cardiac HCN channels to accelerate the heart rate (Brown et al 1979). HCN isoforms are expressed in the brain (Ludwig et al 1998;Santoro et al 1998) where they modulate excitability and action potential firing patterns (reviewed by Shah 2014).…”

Section: Hcn Channelsmentioning

confidence: 99%

Control of neuronal excitability by Group I metabotropic glutamate receptors

Amb

Jds

et al. 2017

Biophys Rev

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Metabotropic glutamate (mGlu) receptors couple through G proteins to regulate a large number of cell functions. Eight mGlu receptor isoforms have been cloned and classified into three Groups based on sequence, signal transduction mechanisms and pharmacology. This review will focus on Group I mGlu receptors, comprising the isoforms mGlu 1 and mGlu 5 . Activation of these receptors initiates both G protein-dependent and -independent signal transduction pathways. The G-protein-dependent pathway involves mainly Gα q , which can activate PLCβ, leading initially to the formation of IP 3 and diacylglycerol. IP 3 can release Ca 2+ from cellular stores resulting in activation of Ca 2+ -dependent ion channels. Intracellular Ca 2+ , together with diacylglycerol, activates PKC, which has many protein targets, including ion channels. Thus, activation of the G-protein-dependent pathway affects cellular excitability though several different effectors. In parallel, G protein-independent pathways lead to activation of non-selective cationic currents and metabotropic synaptic currents and potentials. Here, we provide a survey of the membrane transport proteins responsible for these electrical effects of Group I metabotropic glutamate receptors.

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How does adrenaline accelerate the heart?

Cited by 520 publications

References 9 publications

The carboxyl-terminal region of cyclic nucleotide-modulated channels is a gating ring, not a permeation path

The carboxyl-terminal region of cyclic nucleotide-modulated channels is a gating ring, not a permeation path

5-HT-Induced, 5-HT3 Receptor-Mediated, and Ruthenium Red-and Capsaicin-Sensitive Positive Chronotropic Effects in the Isolated Guinea Pig Atrium

Control of neuronal excitability by Group I metabotropic glutamate receptors

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