Pay attention to potassium channels! First steps in the molecular identification of SK channels and their role in neuronal signal encoding.

May 21, 2000

Researchers at the Max Planck Institute for Experimental Medicine in Göttingen, Germany, have identified a novel potassium current activated by intracellular calcium that shapes the frequency encoding of signals in neurons of the hippocampus (Proc. Natl. Acad. Sci. USA. 96: 4662-4667, 1999). Together with a detailed mapping of the expression of calcium-activated potassium channels (SK channels) in the brain (Mol. Cell. Neurosci., ACADEMIC PRESS), their findings contribute to our understanding of the molecular basis of signal processing in neurons.

Ion channels are the basic elements generating electrical messages that are the units of rapid neural signalling. They are therefore key-molecules in the regulation of membrane excitability and of cell-to-cell communication in the nervous system, ultimately affecting higher processes such as the functional state of the brain (i.e. during sleep, awakeness, arousal, etc.) and the way experience changes the brain.

Potassium channels are structurally among the simplest in their superfamily of ion channels, and are encoded by at least 58 different mammalian genes. The functional meaning of this variety of potassium channels is largely unknown. After their cloning in the last decade, the present challenge is to understand where all these channels are expressed and what they exactly do there. In the case of neuronal potassium channels, this reductionist approach leads from the cloned molecules to the elucidation of how they shape the functional properties of single neurons, and ultimately to their effects on the properties of neuronal networks or even of whole brain regions.

Paola Pedarzani, Martin Stocker and collaborators at the Max Planck Institute for Experimental Medicine in Göttingen have focused on a particular family of potassium channels, the small-conductance calcium-activated potassium channels (SK). These channels are activated by small changes in intracellular calcium levels, thereby integrating variations in the metabolic state of the cell and in its membrane potential. In cortical neurons, SK channels respond to the calcium entering the cell during action potential firing. Their opening makes the neurons to hyperpolarize, thus dramatically slowing down the action potential firing rate. This phenomenon is called "spike frequency adaptation" and plays an important role in neuronal signalling, as neurons use a frequency code to integrate and forward information. Spike frequency adaptation can be shut down by a number of neurotransmitters in the brain. Noradrenaline and other monoamines, for example, are diffusely released when the brain commands arousal and attention, and cause phosphorylation of some component of the SK channel. This reduces the activity of the SK channels underlying a current called sIAHP (s stands for slow), and consequently the late phase of adaptation. As a result, neurons are more excitable and can follow inputs more faithfully. This neuromodulatory effect can be regarded as a molecular correlate of paying attention.

The Göttingen researchers have found that the three members of the SK channel family (SK1, SK2 and SK3) present partially overlapping, but distinct expression patterns in the rat brain.

In the hippocampus, a brain region important for learning, memory consolidation and spatial orientation, pyramidal neurons express all three subunits at different levels. The surprising finding was that the SK2 subunit, which is highly sensitive to the bee-venom toxin apamin, was expressed at high levels in hippocampal pyramidal neurons, where no apamin-sensitive current had been described. Stocker and Pedarzani could identify a novel apamin-sensitive current mediated by SK channels in these neurons and called IAHP. A key-element for this finding was the discovery that this current can be blocked by bicuculline salts, traditionally used to inhibit GABAA receptors. IAHP contributes to the early phase of spike frequency adaptation, and does not seem to be modulated by neurotransmitters as the previously characterized apamin-insensitive sIAHP.

This finding settles a long-lived controversy between results obtained by electrophysiology and apamin-binding studies. Moreover, it provides a potential molecular correlate for the effects of apamin on synaptic plasticity and on hippocampal-dependent learning reported by several groups. Finally, it shows how influx of calcium during action potentials can activate in the same neuron two currents, IAHP and sIAHP, both mediated by SK or SK-like channels, but with different time-courses, pharmacological and modulatory properties and functions. Next question is which molecular mechanisms are at work to couple calcium sources to these different calcium-sensitive effectors in single neurons. The reductionist approach to complex cerebral functions has still a long way to go, but the work of correlation between cloned channels, native currents and their function is allowing the first steps to be taken.


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