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New antiarrhythmic targets to control intracellular calcium handling.

Driessen HE, Bourgonje VJ, van Veen TA, Vos MA - Neth Heart J (2014)

Bottom Line: Drug therapies to prevent SCD do not provide satisfying results, leading to the demand for new antiarrhythmic strategies.New targets include Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII), the Na/Ca exchanger (NCX), the Ryanodine receptor (RyR, and its associated protein FKBP12.6 (Calstabin)) and the late component of the sodium current (I Na-Late ), all related to intracellular calcium (Ca(2+)) handling.These new targets prove to be interesting; however more insight into long-term drug effects is necessary before clinical applicability becomes reality.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Yalelaan 50, 3584 CM, Utrecht, the Netherlands, h.e.driessen@gmail.com.

ABSTRACT
Sudden cardiac death due to ventricular arrhythmias is a major problem. Drug therapies to prevent SCD do not provide satisfying results, leading to the demand for new antiarrhythmic strategies. New targets include Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII), the Na/Ca exchanger (NCX), the Ryanodine receptor (RyR, and its associated protein FKBP12.6 (Calstabin)) and the late component of the sodium current (I Na-Late ), all related to intracellular calcium (Ca(2+)) handling. In this review, drugs interfering with these targets (SEA-0400, K201, KN-93, W7, ranolazine, sophocarpine, and GS-967) are evaluated and their future as clinical compounds is considered. These new targets prove to be interesting; however more insight into long-term drug effects is necessary before clinical applicability becomes reality.

No MeSH data available.


Related in: MedlinePlus

Calcium handling. 0; Sodium enters the cell, creating the AP upstroke. 1; Calcium enters via the LTCC facilitating the plateau phase of the AP and initiating CICR. 2; via RyR on the sarcoplasmic reticulum leading to 3; calcium binding to the contractile elements: excitation-contraction coupling. 4; NCX transports calcium from the cell in exchange for sodium. 5; calcium is pumped back into the SR via SERCA, together with 4 this leads to relaxation of the contractile elements and the end of the plateau phase. 6; Potassium restores the negative membrane potential
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Fig2: Calcium handling. 0; Sodium enters the cell, creating the AP upstroke. 1; Calcium enters via the LTCC facilitating the plateau phase of the AP and initiating CICR. 2; via RyR on the sarcoplasmic reticulum leading to 3; calcium binding to the contractile elements: excitation-contraction coupling. 4; NCX transports calcium from the cell in exchange for sodium. 5; calcium is pumped back into the SR via SERCA, together with 4 this leads to relaxation of the contractile elements and the end of the plateau phase. 6; Potassium restores the negative membrane potential

Mentions: Of the ions involved in the activation of the heart, Ca2+ plays a key role in excitation-contraction. As mentioned, Ca2+ has effects on the membrane potential during the AP plateau via LTCC. LTCC is activated upon depolarisation of the sarcolemma due to a local increase of positive charge that is brought about through influx of [Na+], while LTCC is inactivated by local [Ca2+]i via calmodulin (CaM) binding on the C-terminus of the channel. The initial Ca2+ influx via the LTCC leads to Ca2+ induced calcium release (CICR) from the sarcoplasmic reticulum (SR), which is mediated by the RyRs (reviewed by Bers [8]). When RyR is activated, this leads to Ca2+ extrusion from the SR thereby increasing [Ca2+]i but this increase in Ca2+ also triggers inactivation of the LTCC. The RyR is a channel, but also a scaffolding protein that clusters proteins such as CaM (exerts Ca2+ dependent modulation of RyR and LTCC function, see below), protein kinase A (PKA, which can alter RyR and Ica gating), and sorcin (which connects RyRs and LTCCs) near the Ca2+ release complex. Subsequently, Ca2+ released from the SR binds to troponin to facilitate contraction of the sarcomere, the contractile element of the myocyte. Thus, Ca2+ links the electrical activation of cardiomyocytes to mechanical contraction: excitation-contraction coupling (Fig. 2).Fig. 2


New antiarrhythmic targets to control intracellular calcium handling.

Driessen HE, Bourgonje VJ, van Veen TA, Vos MA - Neth Heart J (2014)

Calcium handling. 0; Sodium enters the cell, creating the AP upstroke. 1; Calcium enters via the LTCC facilitating the plateau phase of the AP and initiating CICR. 2; via RyR on the sarcoplasmic reticulum leading to 3; calcium binding to the contractile elements: excitation-contraction coupling. 4; NCX transports calcium from the cell in exchange for sodium. 5; calcium is pumped back into the SR via SERCA, together with 4 this leads to relaxation of the contractile elements and the end of the plateau phase. 6; Potassium restores the negative membrane potential
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig2: Calcium handling. 0; Sodium enters the cell, creating the AP upstroke. 1; Calcium enters via the LTCC facilitating the plateau phase of the AP and initiating CICR. 2; via RyR on the sarcoplasmic reticulum leading to 3; calcium binding to the contractile elements: excitation-contraction coupling. 4; NCX transports calcium from the cell in exchange for sodium. 5; calcium is pumped back into the SR via SERCA, together with 4 this leads to relaxation of the contractile elements and the end of the plateau phase. 6; Potassium restores the negative membrane potential
Mentions: Of the ions involved in the activation of the heart, Ca2+ plays a key role in excitation-contraction. As mentioned, Ca2+ has effects on the membrane potential during the AP plateau via LTCC. LTCC is activated upon depolarisation of the sarcolemma due to a local increase of positive charge that is brought about through influx of [Na+], while LTCC is inactivated by local [Ca2+]i via calmodulin (CaM) binding on the C-terminus of the channel. The initial Ca2+ influx via the LTCC leads to Ca2+ induced calcium release (CICR) from the sarcoplasmic reticulum (SR), which is mediated by the RyRs (reviewed by Bers [8]). When RyR is activated, this leads to Ca2+ extrusion from the SR thereby increasing [Ca2+]i but this increase in Ca2+ also triggers inactivation of the LTCC. The RyR is a channel, but also a scaffolding protein that clusters proteins such as CaM (exerts Ca2+ dependent modulation of RyR and LTCC function, see below), protein kinase A (PKA, which can alter RyR and Ica gating), and sorcin (which connects RyRs and LTCCs) near the Ca2+ release complex. Subsequently, Ca2+ released from the SR binds to troponin to facilitate contraction of the sarcomere, the contractile element of the myocyte. Thus, Ca2+ links the electrical activation of cardiomyocytes to mechanical contraction: excitation-contraction coupling (Fig. 2).Fig. 2

Bottom Line: Drug therapies to prevent SCD do not provide satisfying results, leading to the demand for new antiarrhythmic strategies.New targets include Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII), the Na/Ca exchanger (NCX), the Ryanodine receptor (RyR, and its associated protein FKBP12.6 (Calstabin)) and the late component of the sodium current (I Na-Late ), all related to intracellular calcium (Ca(2+)) handling.These new targets prove to be interesting; however more insight into long-term drug effects is necessary before clinical applicability becomes reality.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Yalelaan 50, 3584 CM, Utrecht, the Netherlands, h.e.driessen@gmail.com.

ABSTRACT
Sudden cardiac death due to ventricular arrhythmias is a major problem. Drug therapies to prevent SCD do not provide satisfying results, leading to the demand for new antiarrhythmic strategies. New targets include Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII), the Na/Ca exchanger (NCX), the Ryanodine receptor (RyR, and its associated protein FKBP12.6 (Calstabin)) and the late component of the sodium current (I Na-Late ), all related to intracellular calcium (Ca(2+)) handling. In this review, drugs interfering with these targets (SEA-0400, K201, KN-93, W7, ranolazine, sophocarpine, and GS-967) are evaluated and their future as clinical compounds is considered. These new targets prove to be interesting; however more insight into long-term drug effects is necessary before clinical applicability becomes reality.

No MeSH data available.


Related in: MedlinePlus