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Exciting muscles: ion channels and excitation-contraction coupling in exercise and disease

G.D. Lamb, Department of Zoology, La Trobe University, Bundoora, Melbourne, VIC 3086, Australia.

A skeletal muscle fibre is a highly specialised excitable cell with a very ordered structure and many ‘clever’ regulatory mechanisms, which together enable the fibre to synchronously contract throughout its whole length and thickness, time and time again, producing the precise force or movement required, over a brief or a prolonged period as needed. It is some of the exquisite ‘design features’ and regulatory mechanisms of the ion channels and other processes that allow a muscle fibre to accurately and repeatedly perform its demanding function.

The term ‘excitation-contraction coupling’ denotes the complex sequence of events in a muscle fibre (Lamb, 2000) encompassing the following: i) initiation of an action potential in the post-synaptic membrane and its propagation along the surface membrane and into the transverse tubular (t-) system (‘excitation’); ii) activation of the voltage-sensors (dihydropyridine receptors) in the t-system; iii) opening of the ryanodine receptor-Ca2+ release channels (RyRs) in the adjacent sarcoplasmic reticulum (SR) membrane; iv) release of Ca2+ stored in the SR; v) increase in the free [Ca2+] in the cytoplasm; vi) binding of Ca2+ to regulatory sites on troponin-C; and finally vii) force production by the contractile proteins (‘contraction’). This sequence involves the coordinated activation of many different types of ion channels, both voltage-gated and ligand-gated, which depends greatly on their specific characteristics, localization, density and regulatory control.

An interesting question is how the spread of excitation in normal muscle fibres ensures that every region is excited in synchrony without allowing action potentials to re-emerge from the t-system and cause unintended re-excitation (Posterino et al., 2000; Lamb, 2005). Regulation of the Cl- conductance enables the membrane potential to be stabilised and yet excitability to be preserved in the face of repeated excitation and run-down of the K+ gradient (Pedersen et al., 2004; Dutka et al., 2008). The regulatory control of the RyRs, in particular by ATP and cytoplasmic Mg2+, is critical to normal voltage-sensor control of Ca2+ release (Lamb & Stephenson, 1994; Laver et al., 2001) and also plays a pivotal role in reducing SR Ca2+ release in extreme metabolic conditions (Dutka & Lamb, 2004). The latter suggests that the muscle fatigue occurring in some circumstances is possibly simply the consequence of triggering a vital protective mechanism in the cells (Allen et al., 2008). A further important feed-back system operating in muscle regulates the amount of Ca2+ released through the RyRs such that an action potential elicits a set amount of Ca2+ release irrespective of whether the total amount of Ca2+ stored in the SR has increased (Posterino & Lamb, 2003); this helps ensure the muscle fibre produces the desired force response irrespective of any preceding muscle activity. Some of the mechanisms influencing the responsiveness of contractile apparatus can increase as well as decrease responsiveness (Lamb & Posterino, 2003; Murphy et al., 2008).

Allen DG, Lamb GD & Westerblad H. (2008) Physiological Reviews 88, 287–332.

Dutka TL & Lamb GD. (2004) Journal of Physiology, 560, 451-468.

Dutka TL, Murphy RM, Stephenson DG & Lamb GD. (2008) Journal of Physiology 586, 875-887.

Lamb GD. (2000) Clinical and Experimental Pharmacology and Physiology, 27, 216-224.

Lamb GD. (2005) Muscle and Nerve, 31, 652-658.

Lamb GD & Posterino GS. (2003) Journal of Physiology, 546, 149-163.

Lamb GD & Stephenson DG. (1994) Journal of Physiology, 478, 331-339.

Laver DR, Lenz GK & Lamb GD. (2001) Journal of Physiology, 537, 763-778.

Murphy RM, Dutka TL & Lamb GD. (2008) Journal of Physiology, 586, 2203-2216.

Pedersen TH, Nielsen OB, Lamb GD & Stephenson DG. (2004) Science 305, 1144-1147.

Posterino GS & Lamb GD. (2003) Journal of Physiology, 551, 219-237.

Posterino GS, Lamb GD & Stephenson DG. (2000) Journal of Physiology 527, 131-137.