Calmodulin antagonist W7 directly inhibits f-type current in rabbit sino-atrial cells

Chatelier, Aurélien; Renaudon, Barbara; Bescond, Jocelyn; Chemaly, Antoun El; Demion, Marie; Bois, Patrick

doi:10.1016/j.ejphar.2005.08.024

Cited by 9 publications

(8 citation statements)

References 23 publications

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“…As reported for olfactory cyclic nucleotide-activated currents [142], Chatelier et al [141] proposed that the direct inhibition of I f by W7 could be due to an interaction of W7 with the nucleotide binding site located in the C-terminal region of the f-channel. Both effects depend on the W7 concentration, with a maximal effect at 50 M. Furthermore, experiments conducted using low concentrations of free Ca 2+ on the cytoplasmic side of the patch (pCa=10) indicate that the W7 effects are calmodulinindependent.…”

Section: W7mentioning

confidence: 85%

“…5), which is referred to as a calmodulin antagonist, inhibits Ca 2+ /calmodulin-activated phosphodiesterase and myosin light chain kinase [137][138]. As such, W7 has been used as a pharmacological tool to study modulation of the pacemaker current in guinea-pig and rabbit SA node cells [140][141]. As such, W7 has been used as a pharmacological tool to study modulation of the pacemaker current in guinea-pig and rabbit SA node cells [140][141].…”

Section: W7mentioning

confidence: 99%

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Molecular Regulation and Pharmacology of Pacemaker Channels

Bois¹,

Guinamard²,

Chemaly³

et al. 2007

CPD

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The spontaneous activity of cardiac tissue originates in specialized pacemaker cells in the sino-atrial node that generate autonomous rhythmic electrical impulses. A number of regions in the brain are also able to generate spontaneous rhythmic activity to control and regulate important physiological functions. The generation of pacemaker potentials relies on a complex interplay between different types of currents carried by cation channels. Among these currents, the hyperpolarization-activated current (termed I(f), cardiac pacemaker "funny" current, and I(h) in neurons) is the major component contributing to the initiation of cardiac and neuronal excitability and to the modulation of this excitability by neurotransmitters and hormones. I(f) is an inward current activated by hyperpolarization of the membrane potential and by intracellular cyclic nucleotides such as cAMP. The identification at the end of the 1990s of a family of mammalian genes that encode for four Hyperpolarization-activated Cyclic Nucleotide-gated channels, HCN1-4, has made analysis of the location of these channels and the study of their biophysical properties an obtainable goal. As a result, specific agents have been developed for their ability to selectively reduce heart rate by lowering cardiac pacemaker activity where f-channels are their main natural target. These drugs include alinidine, zatebradine, cilobradine, ZD-7288 and ivabradine. Recent data indicate that pharmacological tools such as W7 and genistein, which have been used to identify some intracellular pathways involved in ionic channel modulation, also have the ability to inhibit I(f) directly. This opens new perspectives for the future development of other specific rhythm-lowering agents.

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Section: W7mentioning

confidence: 85%

Section: W7mentioning

confidence: 99%

Molecular Regulation and Pharmacology of Pacemaker Channels

Bois¹,

Guinamard²,

Chemaly³

et al. 2007

CPD

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“…Heath and Hughes, 1971;Chatelier et al, 2005a), but the problem may be more complex than a deficient myocardial oxygen supply. Calcium handling during excitation-contraction coupling and a collapse of adrenergic stimulation, as well as extracellular acidosis and hyperkalemia, have also been implicated (Farrell, 1997;Hanson et al, 2006;Farrell, in press).…”

Section: Introductionmentioning

confidence: 99%

Maximum cardiac performance and adrenergic sensitivity of the sea bassDicentrarchus labraxat high temperatures

Farrell

Axelsson

Altimiras

et al. 2007

Journal of Experimental Biology

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“…Recently, one study from Lakatta group using KN-93, myristoylated AIP, and W-7 to inhibit CaMKII (Yaniv et al, 2013) suggest that CaMKII may affect SAN automaticity by actions on metabolism. In our opinion, these results are intriguing but inconclusive because of the documented off-target actions of these reagents (Ledoux et al, 1999; Chatelier et al, 2005; Gao et al, 2006; Rezazadeh et al, 2006; Liao et al, 2011). Taken together, these studies support a view that CaMKII is not required to maintain basal heart rates but plays a critical role in sustained heart rate increases during physiological stress.…”

Section: Camkii In San Physiologymentioning

confidence: 92%

“…They showed that I f current amplitude was unaffected by the CaMKII inhibitor KN-93 (1 μM) although this CaMKII inhibition did reduce L-type Ca 2 + current by 48 ± 19% at 0 mV voltage clamp command potential. However, a more recent study challenged the concept of calmodulin regulation of I f (Chatelier et al, 2005) based on experiments in inside-out cell membrane macro-patches excised from rabbit SAN cells. They found that “intracellular” calmodulin perfusion had no effect on HCN activity and did not change the cAMP-induced I f activation shift.…”

Section: Camkii In San Physiologymentioning

confidence: 99%

CaMKII in sinoatrial node physiology and dysfunction

Anderson

2014

Front. Pharmacol.

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The calcium and calmodulin-dependent protein kinase II (CaMKII) is present in sinoatrial node (SAN) pacemaker cells and is required for physiological “fight or flight” SAN beating rate responses. Inhibition of CaMKII in SAN does not affect baseline heart rate, but reduces heart rate increases in response to physiological stress. CaMKII senses intracellular calcium (Ca2+) changes, oxidation status, and hyperglycemia to phosphorylate substrates that regulate Ca2+-sensitive proteins, such as L-type Ca2+ channels, phospholamban, and cardiac ryanodine receptors (RyR2). All of these substrates are involved in the SAN pacemaking mechanism. Excessive CaMKII activity, as occurs under pathological conditions such as heart failure, ischemia, and diabetes, can promote intracellular Ca2+ overload and reactive oxygen species production. Oxidation of CaMKII (ox-CaMKII) locks CaMKII into a constitutively active configuration that contributes to SAN cell apoptosis and fibrosis. This ox-CaMKII-mediated loss of functional SAN cells contributes to SAN dysfunction (SND) and sudden death. Thus, CaMKII has emerged as a central regulator of physiological SAN responses and a key determinant of SND.

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Calmodulin antagonist W7 directly inhibits f-type current in rabbit sino-atrial cells

Cited by 9 publications

References 23 publications

Molecular Regulation and Pharmacology of Pacemaker Channels

Molecular Regulation and Pharmacology of Pacemaker Channels

Maximum cardiac performance and adrenergic sensitivity of the sea bassDicentrarchus labraxat high temperatures

CaMKII in sinoatrial node physiology and dysfunction

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