Figure 7.

Figure 7.

(A) Canonical TRP channels can transiently open to allow the passage of Ca²⁺ ions into the interior compartment (left panel). Several mechanisms modulate the activity of the channel: binding of small molecule activators to one of the ligand binding pockets favors the opening event and thereby increases the overall channel activity. In the gating process, the TRP helix (orange) plays a central role as it has a direct connection to the pore-forming helices (blue), constituting the ion-conducting pore. Binding of small molecule inhibitors and the inhibitory protein CaM can restrict the mobility of the TRP helix, thus locking the channel in the closed state (bottom and top panels on the right, respectively). In the latter case, high intracellular Ca²⁺ concentrations cause the Ca²⁺-sensing protein CaM to bind to the CIRB region of the protruding rib-helix (red). This binding event stabilizes a previously disordered region that directly connects to the TRP helix. (B) Individual or simultaneous binding of activators and/or inhibitors modulate the channel gating. Interestingly, modulation sites, i.e. ligand pockets or structural features to which certain compounds or regulatory proteins bind, can accommodate both activators and inhibitors. Thus, these regions can be considered as activity switches. Binding of activators results in an ‘ON’ position, whereas inhibitor binding causes an ‘OFF’ state. In the case that multiple modulators bind simultaneously, all signals are integrated to determine whether the channel opens or remains closed.