SERCAs Sodium-calcium

Schematic diagram of a cardiac muscle sarcomere, with sites of action of several drugs that alter contractility. Na+,K+ ATPase, the sodium pump, is the site of action of cardiac glycosides. NCX is the sodium, calcium exchanger. Cav-L is the voltage-gated, L-type calcium channel. SERCA (sarcoplasmic...

Cardiac glycosides increase contraction of the cardiac sarcomere by increasing the free calcium concentration in the vicinity of the contractile proteins during systole. The increase in calcium concentration is the result of a two-step process first, an increase of intracellular sodium concentration because of Na+,K+ ATPase inhibition and second, a relative reduction of calcium expulsion from the cell by the sodium-calcium exchanger (NCX in Figure 13-1) caused by the increase in intracellular sodium. The increased cytoplasmic calcium is sequestered by SERCA in the SR for later release. Other mechanisms have been proposed but are not well supported. 

It is noteworthy that the inactivation of the Heliothis RyR at millimolar [Ca ] was prevented at all flubendiamide concentrations tested. This could plausibly explain the insecticidal mechanism since deactivation of calcium release channels at high [Ca ] would be essential to terminate the intracellular calcium transient (27). According to this hypothesis, ryanodine receptors would be fixed in the (sub)conductance conformation leading to calcium store depletion and, possibly, to subsequent activation of capacitative calcium entry through plasma membrane channels. This would override compensatory calcium removal mechanisms such as the sarcoplasmic Ca-ATPase (SERCA) activity and the sodium-calcium exchanger (NCX) in the plasma membrmie. The sustained high intracellular [Ca would finally lead to muscle contraction paralysis that is consistently observed in flubendiamide-affected lepidopteran larvae. 

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