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Fulltext Circadian oscillations of cytosolic free calcium regulate the Arabidopsis circadian clock

Martí Ruiz MC, Hubbard KE, Gardner MJ, Jung HJ, Aubry S, Hotta CT, et al.

Nat Plants, 2018 Sep;4(9):690-698.
PMID: 30127410 DOI: 10.1038/s41477-018-0224-8

In the last decade, the view of circadian oscillators has expanded from transcriptional feedback to incorporate post-transcriptional, post-translational, metabolic processes and ionic signalling. In plants and animals, there are circadian oscillations in the concentration of cytosolic free Ca2+ ([Ca2+]cyt), though their purpose has not been fully characterized. We investigated whether circadian oscillations of [Ca2+]cyt regulate the circadian oscillator of Arabidopsis thaliana. We report that in Arabidopsis, [Ca2+]cyt circadian oscillations can regulate circadian clock function through the Ca2+-dependent action of CALMODULIN-LIKE24 (CML24). Genetic analyses demonstrate a linkage between CML24 and the circadian oscillator, through pathways involving the circadian oscillator gene TIMING OF CAB2 EXPRESSION1 (TOC1).

Matched MeSH terms: Calcium/physiology
Extracellular calcium modulates insulin's action on enzymes controlling cyclic AMP metabolism in intact hepatocytes

Irvine F, Wallace AV, Sarawak SR, Houslay MD

Biochem. J., 1993 Jul 01;293 ( Pt 1):249-53.
PMID: 8392336

Absence of physiological concentrations of extracellular Ca2+ in the Krebs-Henseleit incubation buffer did not affect the ability of 10 nM glucagon (< 5%) to increase hepatocyte intracellular cyclic AMP concentrations, but severely ablated (by approximately 70%) the ability of 10 nM insulin to decrease these elevated concentrations. Cyclic AMP metabolism is determined by production by adenylate cyclase and degradation by cyclic AMP phosphodiesterase (PDE). In the absence of added extracellular Ca2+ (2.5 mM), insulin's ability to activate PDE activity was selectively compromised, showing a failure of insulin to activate two of the three insulin-stimulated activities, namely the 'dense-vesicle' and peripheral plasma-membrane (PPM) PDEs. In the absence of added Ca2+, insulin's ability to inhibit adenylate cyclase activity in intact hepatocytes was decreased dramatically. Vasopressin and adrenaline (+ propranolol) failed to elicit the activation of either the 'dense-vesicle' or the PPM-PDEs. The presence of physiological concentrations of extracellular Ca2+ in the incubation medium is shown to be important for the appropriate generation of insulin's actions on cyclic AMP metabolism.

Matched MeSH terms: Calcium/physiology*
Inhibition of calcium-dependent contractions of the isolated guinea-pig ileal longitudinal muscle and taenia coli by the total glycosidic extract of the plant Sarcolobus globosus

Mustafa MR

Toxicon, 1993 Jan;31(1):67-74.
PMID: 8446965

The effect of the total glysosidic extract of the plant Sarcolobus globosus was investigated on the contractions of the smooth muscle of the guinea-pig ileal longitudinal muscle and taenia coli. In the ileal longitudinal muscle, addition of the extract inhibited the electrical field-stimulated twitches. Similarly to verapamil, it also reduced the contractions of the muscle to acetylcholine, histamine and KCl. However, only the tonic contraction to KCl was reversed by increasing the extracellular calcium concentration. In the taenia coli, lower concentrations of both the extract and verapamil induced a parallel displacement of the dose-response curves to calcium (0.30-30 mM). Addition of the extract also dose-dependently inhibited the KCl-induced contraction of the taenia coli. Increasing the calcium concentration increased the IC50 values of the extract. The result suggests that the inhibitory effect of the Sarcolobus globosus extract on the smooth muscle, like verapamil, is mainly due to inhibition of calcium influx.

Matched MeSH terms: Calcium/physiology*
Fulltext Multiple targets for flecainide action: implications for cardiac arrhythmogenesis

Salvage SC, Chandrasekharan KH, Jeevaratnam K, Dulhunty AF, Thompson AJ, Jackson AP, et al.

Br J Pharmacol, 2018 Apr;175(8):1260-1278.
PMID: 28369767 DOI: 10.1111/bph.13807

Flecainide suppresses cardiac tachyarrhythmias including paroxysmal atrial fibrillation, supraventricular tachycardia and arrhythmic long QT syndromes (LQTS), as well as the Ca2+ -mediated, catecholaminergic polymorphic ventricular tachycardia (CPVT). However, flecainide can also exert pro-arrhythmic effects most notably following myocardial infarction and when used to diagnose Brugada syndrome (BrS). These divergent actions result from its physiological and pharmacological actions at multiple, interacting levels of cellular organization. These were studied in murine genetic models with modified Nav channel or intracellular ryanodine receptor (RyR2)-Ca2+ channel function. Flecainide accesses its transmembrane Nav 1.5 channel binding site during activated, open, states producing a use-dependent antagonism. Closing either activation or inactivation gates traps flecainide within the pore. An early peak INa related to activation of Nav channels followed by rapid de-activation, drives action potential (AP) upstrokes and their propagation. This is diminished in pro-arrhythmic conditions reflecting loss of function of Nav 1.5 channels, such as BrS, accordingly exacerbated by flecainide challenge. Contrastingly, pro-arrhythmic effects attributed to prolonged AP recovery by abnormal late INaL following gain-of-function modifications of Nav 1.5 channels in LQTS3 are reduced by flecainide. Anti-arrhythmic effects of flecainide that reduce triggering in CPVT models mediated by sarcoplasmic reticular Ca2+ release could arise from its primary actions on Nav channels indirectly decreasing [Ca2+ ]i through a reduced [Na+ ]i and/or direct open-state RyR2-Ca2+ channel antagonism. The consequent [Ca2+ ]i alterations could also modify AP propagation velocity and therefore arrhythmic substrate through its actions on Nav 1.5 channel function. This is consistent with the paradoxical differences between flecainide actions upon Na+ currents, AP conduction and arrhythmogenesis under circumstances of normal and increased RyR2 function.
LINKED ARTICLES: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

Matched MeSH terms: Calcium/physiology
Roselle Polyphenols Exert Potent Negative Inotropic Effects via Modulation of Intracellular Calcium Regulatory Channels in Isolated Rat Heart

Lim YC, Budin SB, Othman F, Latip J, Zainalabidin S

Cardiovasc Toxicol, 2017 Jul;17(3):251-259.
PMID: 27402292 DOI: 10.1007/s12012-016-9379-6

Roselle (Hibiscus sabdariffa Linn.) calyces have demonstrated propitious cardioprotective effects in animal and clinical studies; however, little is known about its action on cardiac mechanical function. This study was undertaken to investigate direct action of roselle polyphenols (RP) on cardiac function in Langendorff-perfused rat hearts. We utilized RP extract which consists of 12 flavonoids and seven phenolic acids (as shown by HPLC profiling) and has a safe concentration range between 125 and 500 μg/ml in this study. Direct perfusion of RP in concentration-dependent manner lowered systolic function of the heart as shown by lowered LVDP and dP/dtmax, suggesting a negative inotropic effect. RP also reduced heart rate (negative chronotropic action) while simultaneously increasing maximal velocity of relaxation (positive lusitropic action). Conversely, RP perfusion increased coronary pressure, an indicator for improvement in coronary blood flow. Inotropic responses elicited by pharmacological agonists for L-type Ca2+channel [(±)-Bay K 8644], ryanodine receptor (4-chloro-m-cresol), β-adrenergic receptor (isoproterenol) and SERCA blocker (thapsigargin) were all abolished by RP. In conclusion, RP elicits negative inotropic, negative chronotropic and positive lusitropic responses by possibly modulating calcium entry, release and reuptake in the heart. Our findings have shown the potential use of RP as a therapeutic agent to treat conditions like arrhythmia.

Matched MeSH terms: Calcium/physiology