A-to-I RNA editing: effects on proteins key to neural excitability

Abstract

RNA editing by adenosine deamination is a process used to diversify the proteome. The expression of ADARs, the editing enzymes, is ubiquitous among true metazoans, and so adenosine deamination is thought to be universal. By changing codons at the level of mRNA, protein function can be altered, perhaps in response to physiological demand. Although the number of editing sites identified in recent years has been rising exponentially, their effects on protein function, in general, are less well understood. This review assesses the state of the field and highlights particular cases where the biophysical alterations and functional effects caused by RNA editing have been studied in detail.

Figure 1. Edited Mammalian AMPA Receptors Are Impermeable to Ca²⁺

Depicted are two versions of a heteromeric AMPA receptor, each showing two of the four subunits that make up a functional receptor. The transmembrane regions of the subunits are shown as cylinders, the re-entrant channel loop with the typical α-helical segment and the functionally critical Q/R site line the ion channel. Extracellular and intracellular subunit portions are sketched. The filled dot in the extracellular region of GluA2, between transmembrane segments 3 and 4, denotes the R/G edit (see text). The receptor version depicted on the left corresponds to the most prevalent AMPA channel in the brain, composed of the subunits GluA1 and GluA2, the latter edited in the Q/R site of the channel segment M2. The version on the right is the same channel except that the Q/R site of GluA2 is unedited, thus having the exonically encoded GluA2 sequence. This receptor is probably never expressed normally and can only be generated by gene manipulation. The characteristic property differences of the two AMPA receptor versions are listed below the channels, along with consequences on circuits and CNS disease for the unedited receptor. A role for the unedited form in sporadic ALS is presently an attractive hypothesis under debate.

Figure 2. Edited Mammalian Potassium Channels Recover More Quickly from Inactivation

Fast inactivation in voltage-dependent potassium channels is caused by a tethered inactivation particle, which enters the channel’s inner vestibule after opening and plugs the ion conduction pathway by binding to a receptor through a hydrophobic interaction. In the case of human K_v1.1, the inactivation particle is attached to a β subunit. RNA editing reduces the hydrophobicity of the inactivation particle’s receptor, allowing the particle to unbind more rapidly. The dashed arrow indicates a slower rate. The channel’s gate, in the open position, is shown in black.

Figure 3. Edited Squid Na⁺/K⁺ Pumps Release Na⁺ to the Outside More Quickly

States involved in the sequential release of three Na⁺ ions to the outside are depicted. State names are written below each cartoon where P indicates phosphorylation, E1 indicates ion binding sites facing inward, E2 indicates ion binding sites facing outwards, and parentheses indicate occlusion. States that involve K⁺ movement, or ion binding/release to the inside, have been left out. States colored in red indicate a relatively high occupancy, and those in blue a relatively low occupancy. Na⁺ ions are shown in green. The overall effect of editing is to reduce the pumps inhibition from high concentrations of extracellular Na⁺ and negative voltages, leading to faster Na⁺ release and turnover over the physiological range of voltages. The dashed arrow indicates a slower rate.

Figure 4. Edited Octopus Potassium Channels Close More Quickly

Editing of octopus K_v1.1 at position I321V in the fifth transmembrane span destabilizes the open state, allowing the channels to close rapidly upon repolarization. The overall physiological effect would be to reduce the length of the afterhyperpolarization, allowing higher firing frequencies. Because this site is highly edited in polar species and scarcely edited in tropical species, it is hypothesized to be an adaptation to temperature. The dashed arrow indicates a slower rate.