Numerous regulators of back-propagating action potentials, regulating LTP induction by controlling voltage-dependent NMDA receptor activation.
Moreover, this type of regulatory mechanism is subject to modulation by cellular signal transduction cascades. Dax Hoffman and Jeff Magee, working in Dan Johnston's laboratory, found that activation of PKA or PKC shifts the activation curve of A-type K+ currents recorded in hippocampal area CA1 dendrites (32). The voltage-dependence of their activation is shifted in the depolarizing direction, leading to increases in dendritic excitability and increased back-propagating action potentials in dendrites. More recent work by Dan's group, some of it in collaboration with Paige Adams in my lab, has shown that the alterations in A-current voltage-dependence caused by application of PKA, PKC, or P-adrenergic receptor activators is secondary to activation of ERK MAP kinase (33, 34). Overall, these observations indicate that K channel regulation of dendritic membrane properties is regulated by cell surface neurotransmitter receptors coupled to ERK activation. The implication of this, as will be discussed in more detail later, is that neuromodulation of K channel function could serve a critical role in controlling action potential back-propagation and local membrane electrical properties. This mechanism would then allow indirect but critical control over the membrane depolarization necessary for NMDA receptor activation.
What is the molecular basis for this regulation of voltage-dependent K channel function? The A-type potassium channel pore-forming subunit Kv4.2 is localized to subsynaptic compartments of dendrites in CA1 pyramidal neurons and is likely the pore-forming subunit of dendritic A-type channels in these regions.
Morover, Paige Adams in my laboratory tested the idea that Kv4.2 might be a target for ERK, and found that Kv4.2 is a substrate for ERK in hippocampal pyramidal neurons
(35). In additional recent studies in collaboration with Lilian Yuan in Dan Johnston's lab, we found that activation of PKA and PKC, as well as stimulation of P-adrenergic receptors, leads to ERK activation and Kv4.2 phosphorylation by ERK in hippocampal area CA1 (33). Furthermore, in these studies, we found that modulation of A currents by PKA, PKC, and beta-adrenergic receptors are secondary to ERK activation, and that this mechanism is a basis for controlling back-propagating action potentials in pyramidal neuron dendrites.
Our working hypothesis is that ERK phosphorylation of Kv4.2, the K+ channel pore-forming subunits likely to mediate A currents in hippocampal dendrites, decreases the probability of channel opening or the number of channels in the membrane. Once these channels in a particular region of a dendrite are rendered nonfunctional as a result of phosphorylation, the ability of a back-propagating action potential to invade that particular dendrite increases. This will allow, or increase the likelihood of, NMDA receptor activation and Ca2+ influx locally, and thus control the induction of LTP at that synapse.
Available data suggest the particular importance of this mechanism in theta-type LTP induction protocols (2, 3). Theta-frequency stimulation causes complex spike bursting in area CA1 cells, which can back-propagate into the dendrites and depolarize synapses. Several groups, including the laboratories of Eric Kandel, Danny Winder, and Tom O'Dell have shown that blocking ERK activation in mouse area CA1 blocks not only the complex spike bursting seen with the theta-frequency stimulation protocol, but also the LTP that is so induced (2, 3). It seems likely that blocking ERK in these experiments decreases the phospho-rylation of Kv4.2, leading to an increase in the probability of current flux through these channels. Moreover, Danny Winder's group has found that beta-adrenergic receptor-mediated modulation of LTP induced with theta-frequency stimulation is blocked by inhibitors of ERK activation. Again, these findings are consistent with a model wherein ERK regulation of membrane electrical properties, via control of Kv4.2 channels, regulates back-propagating action potentials and controls NMDA receptor activation.
Finally, I should note that Anne Anderson, Laura Schrader, and their colleagues in my lab have found evidence that Kv4.2 is a substrate for three different kinases known to be involved in LTP induction: PKC, PKA, and ERK (33, 35). Thus, Kv4.2 may serve as a functional integrator of the actions of these protein kinases by serving as a convergence point for their actions. PKA, PKC, and ERK all lead to a diminution of Kv4.2 function, actions that will tend to promote LTP induction through the mechanisms outlined previously.
The "H" Current
My long-time colleague Dan Johnston told me recently that even hard-core cellular physiologists have a hard time understanding "H" currents, so the odds of a biochemist like me understanding them were slim. He was right. I do know that the
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