How is SR calcium release in muscle modulated by PIP ( 4 , 5 ) 2 ?

Ion channels are embedded in the lipid bilayer of cell membranes; therefore, it is not surprising that their functions can be modulated by membrane phospholipids and their metabolites. Over the last decade, a number of ion channels—including multiple types of potassium channels, voltage-gated calcium channels, and transient receptor potential channels—have been shown to be modulated by phospholipids. This lipid modulation of ion channels has been implicated in the regulation of such neuronal functions as excitability and synaptic transmission. In a recent article published in The Journal of General Physiology, the research team of Vincent Jacquemond demonstrated that phosphoinositides modulate skeletal muscle calcium signaling (Berthier et al., 2015). Surprisingly, their results indicate that phosphoinositides can enhance calcium release from the SR without affecting currents through voltage-gated calcium channels. Excitation–contraction (EC) coupling is the process whereby membrane depolarization in muscle is converted into a transient increase in the cytoplasmic free calcium concentration (Melzer et al., 1995), with the magnitude of the calcium signal determining the force of muscle contraction. In both skeletal and cardiac muscle, EC coupling relies on the close interaction of two calcium channels: a voltage-gated calcium channel (CaV1) in the plasma membrane and T-tubules, and a ryanodine receptor calcium release channel (RyR) in the SR. In cardiac muscle cells, CaV1.2 calcium channels open during the action potential; the resulting calcium influx contributes to the myoplasmic calcium signal and activates the type 2 RyR (RyR2) calcium release channel to trigger further release of calcium from the SR. Thus, in cardiac muscle, the magnitude of the calcium transient is directly related to that of the L-type calcium current. Consequently, modulation of the voltage-gated calcium channel CaV1.2 is an efficient mechanism to regulate cardiac contraction. In adult skeletal muscle, on the other hand, L-type calcium currents contribute little if anything to the myoplasmic calcium signal that controls contraction. Rather, the CaV1.1 isoform acts solely as a voltage sensor (Ríos et al., 1992) that activates the type 1 RyR (RyR1) through conformational coupling. Voltage-dependent activation of RyR1 relies on the cytoplasmic II–III loop of the CaV1.1 1S subunit (Grabner et al., 1999) and on the auxiliary