Figure 9.

Schematic representation of the mitochondrial import pathway for Kv1.3. The Kv1.3 channel is cotranslated by ER-linked and cytosolic ribosomes. ER ribosomes synthesize the plasma membrane Kv1.3, which interacts early with ancillary proteins, such as Kvβ subunits and caveolin, and is routed to the cell surface via COPII-dependent anterograde trafficking. The yellow circle restrains anterograde trafficking to the plasma membrane. Alternatively, (1) the Kv1.3 mRNA, which is translated by cytosolic ribosomes, follows the mitochondrial route. (2) By interacting with channel hydrophobic domains, cytosolic chaperones and cochaperones provide Kv1.3 with a partially folded state competent for mitochondrial translocation. Sequential transmembrane domains from the N- to C-terminus cooperate to achieve the proper folded state. (3) TOM receptors recognize cytosolic Kv1.3. (4) The TOM40 channel at the OMM translocates Kv1.3 to the TIM complex at the IMM. Finally, (5) the TIM50 receptor facilitates Kv1.3 translocation through the TIM23/17 channel into the IMM (6). Spatial and temporal mechanisms defining Kv1.3 membrane topology and tetramerization at the IMM remain unknown.