Downregulation of Transient K⁺Channels in Dendrites of Hippocampal CA1 Pyramidal Neurons by Activation of PKA and PKC

TLDR

Transient A‑type K⁺ channels densely populate distal dendrites of CA1 pyramidal neurons, shaping EPSPs, limiting back‑propagation of action potentials, and preventing dendritic AP initiation, making their modulation by protein kinases of significant interest. The study aimed to determine how activation of PKA and PKC affects these transient K⁺ channels. Using cell‑attached patch recordings from distal dendrites, the authors applied membrane‑permeant PKA activators (8‑bromo‑cAMP or forskolin) and phorbol esters to activate PKC. Both PKA and PKC activation produced a ~15 mV depolarizing shift in the activation curve of transient channels without altering the sustained component, down‑regulating these channels and increasing the amplitude of back‑propagating action potentials, thereby enhancing dendritic excitability.

Abstract

We have reported recently a high density of transient A-type K + channels located in the distal dendrites of CA1 hippocampal pyramidal neurons and shown that these channels shape EPSPs, limit the back-propagation of action potentials, and prevent dendritic action potential initiation (Hoffman et al., 1997). Because of the importance of these channels in dendritic signal propagation, their modulation by protein kinases would be of significant interest. We investigated the effects of activators of cAMP-dependent protein kinase (PKA) and the Ca 2+ -dependent phospholipid-sensitive protein kinase (PKC) on K + channels in cell-attached patches from the distal dendrites of hippocampal CA1 pyramidal neurons. Inclusion of the membrane-permeant PKA activators 8-bromo-cAMP (8-br-cAMP) or forskolin in the dendritic patch pipette resulted in a depolarizing shift in the activation curve for the transient channels of ∼15 mV. Activation of PKC by either of two phorbol esters also resulted in a 15 mV depolarizing shift of the activation curve. Neither PKA nor PKC activation affected the sustained or slowly inactivating component of the total outward current. This downregulation of transient K + channels in the distal dendrites may be responsible for some of the frequently reported increases in cell excitability found after PKA and PKC activation. In support of this hypothesis, we found that activation of either PKA or PKC significantly increased the amplitude of back-propagating action potentials in distal dendrites.