K2P potassium channels regulate cellular excitability using their selectivity filter (C-type) gate. C-type gating mechanisms, best characterized in homotetrameric potassium channels, remain controversial and are attributed to selectivity filter pinching, dilation, or subtle structural changes. The extent to which such mechanisms control C-type gating of innately heterodimeric K2Ps had been unknown. Here, using molecular dynamics and electrophysiology of TREK-1 (K2P2.1) I uncover unprecedented, asymmetric, potassium-dependent conformational changes that underlie K2P C-type gating. These asymmetric order-disorder transitions, enabled by the K2P heterodimeric architecture, encompass pinching and dilation, disrupt the S1 and S2 ion binding sites, require the uniquely long K2P SF2-M4 loop and conserved “M3 glutamatenetwork,” and are suppressed by the K2P C-type gate activator ML335. These findings demonstrate that two distinct C-type gating mechanisms can operate in one channel and underscore the SF2-M4 loop as a target for K2P channel modulator development. In addition, it has long been established that TREK family K2P channels are regulated by plasma membrane phospholipids like PIP2. However, the exact lipid binding sites are unknown and even the directionality of regulation by PIP2 remains controversial, and thus the molecular details of regulation have been left unclear. Here, using coarse-grained molecular dynamics simulations, I identify 3 distinct lipid binding sites on the surface of TREK-1 and establish their relative binding affinities for PIP2. Two of these sites directly contact the well-known regulatory ‘proximal C-terminus’ domain of TREK-1. Subsequently, using all-atom computational electrophysiology simulations, I establish that PIP2 binding to these two sites, as well as basic residue neutralizing mutations, all increase the TREK-1 conduction rate via an electrostatic ion recruitment mechanism. These conditions also alter the distribution of K+ ion in the selectivity filter in ways that likely stabilize the C-type gate active state and lead to higher channel open probability. Finally, my results suggest that PIP2 binding at one of these sites may induce conformational changes that allosterically inactivate the C-type gate, opening the door to resolving previous controversies about the direction of TREK channel regulation by PIP2.