What does type A mean to a pyramidal cell?

Abstract

Potassium channels powerfully control neuronal excitability and exhibit great molecular diversity. Despite this diversity, classification of voltage-gated potassium currents is often simplified into a distinction between a rapidly activating, transient A-type current and a slowly activating and inactivating delayed rectifier (DR) current. However, individual neurons express multiple potassium channel subunits from several families and knowing the functional roles of each of these subunits is essential to understanding neural computations and pathophysiology. As an example, components of the A-type current in neocortical pyramidal cells are generated by Kv4.2, Kv4.3 and Kv1.4 α subunits (Norris & Nerbonne, 2010). In this issue of The Journal of Physiology, Carrasquillo et al. (2012) address the functional roles of each of these subunit types with slice recordings from visual cortex of mice where Kv4.2 (Kv4.2−/−), Kv4.3 (Kv4.3−/−), or Kv1.4 (Kv1.4−/−) subunit protein was eliminated. The consequences of null mutations differed between the three subunits, suggesting distinct roles in regulating membrane properties (Fig. 1). Figure 1 Functional roles of Kv4.2, Kv4.3 and Kv1.4 subunits in neocortical pyramidal neurons (determined by Carrasquillo et al. 2012) In pyramidal neurons from Kv4.2−/− mice, input resistance was increased, the current threshold for action potential (AP) generation was reduced, APs were broader and rebound firing in response to prolonged hyperpolarization was increased. Cells from Kv4.3−/− mice also exhibited increased spike width, but input resistance, current threshold and rebound firing were unchanged. These data suggest greater importance of Kv4.2 at subthreshold voltages, perhaps due to a more hyperpolarized activation range. Elimination of either Kv4.2 or Kv4.3 resulted in faster firing than wild-type neurons but changes in the Kv4.3−/− cells were not significant until larger current injections. In contrast, the Kv4.2−/− cells exhibited greater effects to small current injections than larger ones. The reduced effect of Kv4.2−/− on firing in response to large stimuli may reflect slower recovery from inactivation of Kv4.2 channels. The effects of removing Kv4.2 and Kv4.3 were generally additive, although spike doublets were observed in some of the double cells lacking both Kv4.2 and Kv4.3. These findings allow consideration of whether Kv4 channels normally exist as homomeric or heteromeric channels in pyramidal cells. Previous studies suggested that Kv4.2 and Kv4.3 α subunits form heteromultimers but the present results show differential effects of removal of Kv4.2 and Kv4.3, suggesting that not all channels contain both subunits or that the heteromeric channels have different properties than homomeric channels. It remains to be determined whether the differential effects of subunit removal reflect the elimination of homomeric channels with different biophysical properties, replacement of heteromeric Kv4.2/Kv4.3 channels with homomers, or changes in channel targeting as a result of subunit removal. Carrasquillo et al. (2012) found no significant differences in input resistance, current thresholds, or firing rate in the Kv1.4 −/− mouse; however, pharmacological block of Kv4-mediated A currents with Ba2+ unmasked contributions of Kv1.4 to input resistance, AP current threshold, and repetitive firing. Interestingly, APs were actually narrower in Kv1.4−/− cells, apparently due to a compensatory increase in Kv4.2 channels. It is unclear if upregulation of Kv4.3 or Kv1.4 subunits also occurs with Kv4.2 elimination, but previous studies suggest functional compensation by the DR current. For example, Yuan et al. (2005) reported the absence of A-type current and slower AP repolarization with acute reduction of Kv4.2 channels. In contrast, in most cells from animals lacking Kv4.2 from birth the A-type current was absent yet AP repolarization was normal (Nerbonne et al. 2008). An increased DR current was observed in cells from the Kv4.2−/− animals and this was apparently able to fully compensate for AP repolarization. It was subsequently observed that partial block of the DR with TEA in Kv4.2−/− cells unmasked A-type currents mediated by Kv4.3 and Kv1.4 subunits (confirmed with Kv4.3−/− and Kv1.4−/− animals: Norris & Nerbonne, 2010). Collectively, these observations suggest that long-term elimination of an A-type current component may lead to compensatory changes in other A-type channels or other types of potassium channel. This obviously complicates the interpretation of findings in –/– animals and underscores the need to understand the rules by which such compensatory changes may occur. While the present results concentrate on somatodendritic channels, functional roles of A-type channels depend upon the precise location of their expression. It is not clear to what degree channel localization is altered in the –/– animals. The effectiveness of functional compensation may also vary in different cellular compartments. Still to be resolved is how much natural variation exists in the expression of Kv1.4, Kv4.2, and Kv4.3 and how this relates to known differences in active properties of pyramidal cell populations defined by layer, gene expression, or projection targets (cf. Hattox & Nelson, 2007). With this comprehensive series of papers, Nerbonne and colleagues show us just how complex the molecular basis and functional consequences can be for the seemingly simple type A current.