Stretching and setting boundaries

This month's installment of Generally Physiological considers a channel in skeletal muscle and a cardiac G pro-tein–coupled receptor (GPCR) that are sensitive to mechanical stress as well as their respective ligands, and how the geometry of subcellular domains influences GPCR dynamics. Stretching the boundaries of nAChR gating Although ion channels are often broadly classified as " voltage-gated " or " ligand-gated, " they can also respond to various other stimuli—such as light or stretch—and gating of a particular channel can be influenced by more than one modality. The nicotinic ace-tylcholine receptor (nAChR) that mediates excitatory transmission at the vertebrate neuromuscular junction is among the most familiar of the ligand-gated channels. Noting that mecha-nosensitive channels are abundant in skeletal muscle, and that the nAChR is subject to stretch associated with muscle contraction, Pan et al. (2012) explored the possibility that gating of this prototypical " ligand-gated channel " might be sensitive to mechanical stress. Patch-clamp analysis of endog-enous nAChRs in cultured Xenopus laevis muscle cells or C2C12 myo-tubes, or heterologously expressed in HEK293T cells, indicated that membrane stretch enhanced ACh-dependent nAChR activity without affecting the amplitude of single-channel currents. Further analyses of nAChRs expressed in HEK293T cells implicated both the membrane microenviron-ment and the cytoskeleton in nAChR mechanosensitivity. nAChR activity was less sensitive to mechanical forces when membrane cholesterol was depleted, and more sensitive after exposure to lysophosphatidylcholine, suggesting a role for the lipid bilayer; disruption of the cytoskeleton with latrunculin A or cytochalasin D decreased nAChR mechanosensitivity, suggesting a role for the cytoskeleton. The mechanosensitivity of heterolo-gously expressed nAChRs was greater than that of endogenous nAChRs and, intriguingly, coexpression of rapsyn (a protein essential for nAChR clustering at the neuromuscular junction) decreased nAChR mechanosensitiv-ity, an effect that involved both the rapsyn nAChR-binding domain and the cytoskeleton. The authors thus concluded that both the membrane lipid environment and the actin cy-toskeleton participate in regulation of nAChR mechanosensitivity and hypothesized that rapsyn—by linking nAChR to the cytoskeleton— may limit its mechanosensitivity and thereby protect muscle fiber integrity under conditions of high mechanical stress. Scimia et al. (2012) describe another stretch-sensitive ligand-activated re-ceptor—in this case, not a channel but a GPCR. The apelin receptor APJ, like various other GPCRs, has been implicated in the regulation of cardiac function, suggesting that APJ— or its peptide ligand apelin—might provide therapeutic targets. Surprisingly , Scimia et al. (2012) found that, whereas mice lacking APJ were resistant …