Table 1.
Ion channels and their endocytic pathways.
| Ion Channel | Type of Endocytosis | Stimulus of Internalization | Ubiquitination | Rabs | Associated Pathologies |
|---|---|---|---|---|---|
| ENaC | CME [12] | Kidney: Basal conditions (low aldosterone) [75] Alveoli: hypercapnia [110] |
Polyubiquitination [74] E3 Nedd4-2 [75] DUB USP2-45 [82,83] |
Rab4 [111] Rab11 [108] |
Liddle’s syndrome [69] |
| Nav family (Nav1.1-1.3 and 1.5-1.8) |
ND | ND | Polyubiquitination E3 Nedd4-2 [63] |
ND | Congenital type 3 long QT syndrome # (Nav1.5) [71] Neuropathic pain (Nav1.7-1.8) [76] |
| Kv1.2 | CME, RhoA and cholesterol-dependent [45] | Constitutive [45] and Receptor-mediated: mAChR [112] and EGFR [113] |
ND | ND | ND |
| Kv1.3 | CME [13,52] | Receptor-mediated (EGFR) [52] and PKC [13] | Polyubiquitination E3 Nedd4-2 * [13,64,77] |
ND | ND |
| Kv1.5 | CME ‡ [97] Caveolin-mediated [114] |
Receptor-mediated (5-HT) [114], Drug-induced (quinidine) [56], PKC and AMPK [115] | Ubiquitination E3 Nedd4-2 * [78] |
Rab4, Rab5, Rab7, Rab11 [97] |
ND |
| Kv7.1 | CME [14] | Receptor-mediated (α1AR) [14] and PKC [116] | Polyubiquitination E3 Nedd4-2 [14,65] DUB USP2-45 and USP2-63 [84] |
Rab5, Rab11 [103] |
Type 1 long QT syndrome [117] |
| Kv7.2/7.3 | CME [118] | Receptor and calpain-mediated (NMDA—high glutamate) [118] | Polyubiquitination E3 Nedd4-2 [66] DUB USP36 [119] |
ND | ND |
| Kv11.1 | Caveolin [57,58] ARF6-mediated [48] |
Drug (Desipramine) [55] and Low K+-induced [57] | Monoubiquitination E3 Nedd4-2 [67] |
Rab4 [99] Rab11 [107] | Acquired long QT syndrome [55] |
| Kir1.1 (ROMK) |
CME [24] Caveolin-mediated [44] |
Constitutive [24], WNK [24] and PTK kinases [120] | Monoubiquitination [120] E3 Nedd4-2 * [121] CIE: E3 POSH [122] |
ND | ND |
| Kir2.3 | CME [17] | Constitutive [17] | ND | Rab11 [123] | ND |
| Kir3.1/3.2 | CME [90] | Receptor-mediated (DOR) [90] | ND | Rab7 [124] | ND |
| Kir3.4 | ARF6-mediated [46] | ND | ND | Rab7 [124] | ND |
| Kir6.1 | Caveolin-mediated [40] | PKC [40] | ND | ND | ND |
| Kir6.2 | CME [7] | PKC [125] | Ubiquitination [126] | Rab7 [125] |
Permanent neonatal diabetes mellitus [7] |
| CFTR | CME [15] | ND | Polyubiqutination E3 CHIP [127], c-Cbl [80] and Nedd4-2 * (ΔF508) [128] DUB USP10 [85] |
Rab4, Rab5, Rab7, Rab11 [100] |
ND |
| CLC-2 | Dynamin-dependent [129] | ND | Polyubiquitination E3 Nedd4-2 * [62] |
Rab5, Rab11 [129] | ND |
| TRPC1 | ARF6-mediated [98] | ND | ND | Rab4, Rab5 [98] | ND |
| TRPV4 | CME ‡ [92] | Receptor-mediated (AT1R) [92] | Ubiquitination E3 AIP4 [92] |
ND | ND |
| TRPV5 | CME [42] Caveolin-mediated [41] |
Constitutive [41] | E3 Nedd4-2 * [130] | Rab11 [42] | ND |
| Cav1.2 | CME [16] | Receptor-mediated: AT1R [91] and ERα [131] | Polyubiquitination E3 Mdm2 [131] |
Rab11 [16] | ND |
ND: not determined. * Channels without PY motif. # Congenital type 3 long QT syndrome: Evidence in heterologous system but not in animals. ‡ Indirect evidence.