SK channels in excitability, pacemaking and synaptic integration

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Small conductance calcium-activated potassium channels link elevations of intracellular calcium ions to membrane potential, exerting a hyperpolarizing influence when activated. The consequences of SK channel activity have been revealed by the specific blocker apamin, a peptide toxin from honeybee venom. Recent studies have revealed unexpected roles for SK channels in fine-tuning intrinsic cell firing properties and in responsiveness to synaptic input. They have also identified specific roles for different SK channel subtypes. A host of Ca2+ sources, including distinct subtypes of voltage-dependent calcium channels, intracellular Ca2+ stores and Ca2+-permeable ionotropic neurotransmitter receptors, activate SK channels. The macromolecular complex in which the Ca2+ source, SK channels and various modulators are assembled determines the kinetics and consequences of SK channel activation.

Introduction

Small conductance calcium-activated potassium (SK) channels are voltage-independent and activated solely by intracellular Ca2+. Three different genes express SK channel subunits in overlapping but distinct patterns in the mammalian brain (SK1, SK2, and SK3), whereas a fourth member of the family, IK1 (SK4), is restricted to peripheral tissues and is not covered in this review. Functional SK channels are heteromeric complexes with constitutively bound calmodulin (CaM); channel opening occurs in response to Ca2+ binding to CaM. Importantly, native and cloned SK channels are the only known targets for the bee venom toxin apamin, which blocks the channels with high affinity (KD values ranging from ∼50pM to ∼25nM, depending on subunit composition), and it is very likely that the neuronal and behavioral effects of apamin can be attributed to SK channel blockade [1].

In many neurons, SK channels have a fundamental role in influencing neuronal excitability. SK channels are activated by the transient elevation of intracellular Ca2+ that occurs during an action potential, and their activity contributes to a prolonged afterhyperpolarization (AHP) during which the return to baseline reflects the decay of intracellular Ca2+ levels.

In the past several years the availability of clones for all four of the SK channels [2, 3, 4] has provided not only detailed insights into the biophysical profile of channel gating but also nucleic acid and antibody probes for determination of cellular and subcellular localizations, microdomain organization and developmental profiles. Intensive studies have revealed unexpected roles for SK channels in defining intrinsic cell firing properties, regulating local dendritic Ca2+ transients and affecting synaptic plasticity.

Different neuronal populations have exploited the SK-mediated link between elevated Ca2+ and membrane potential in specific ways. The emerging theme is that physiological variations are accomplished by the composition of the SK channel molecular neighborhood, the microdomain, in which different Ca2+ sources serve to activate SK channels. These macromolecular complexes might include the Ca2+ source in addition to modulatory proteins, and the explicit spatial dimensions endow the kinetics of SK channel effects as well as enabling rapid modulation.

At least four models of SK channel function in different cell types in the CNS can be drawn from recent work. First, in cells such as hippocampal and cortical pyramidal neurons, which are essentially silent in the absence of synaptic input, increased intracellular Ca2+ during synaptic stimulation or action potential firing activates SK channels. Distinct subcellular populations of channels dampen membrane excitability, contribute to dendritic integration and modulate the induction of synaptic plasticity. Second, in tonically firing cells such as ventral midbrain dopamine neurons, SK channels participate in pacemaking by decreasing inter-spike variability and engendering precise tonic firing that responds bi-directionally to synaptic input. Third, in cells that intrinsically fire at high frequencies, such as cerebellar Purkinje neurons, SK channel activity might be necessary for continued firing and modulation of SK channel activity might effect the normally rhythmic firing behavior. Fourth, coupling of SK channels to Ca2+ permeable ionotropic neurotransmitter receptors can lead to a non-typical fast or slow inhibitory response to a normally excitatory neurotransmitter. This review discusses these newly appreciated roles for SK channels in prototypic neurons.

Section snippets

Model 1: SK channels contribute to the AHP and to synaptic integration

In principal neurons of the hippocampus and neocortex, a complex Ca2+-dependent AHP follows one or more action potentials. The AHP includes apamin-sensitive and apamin-insensitive Ca2+-activated K+-selective components, and the contribution of SK channels to these distinct conductances has been controversial (see Figure 1ai) [5]. Recently, through studies of SK knock out (KO) mice [6] or by transgenic expression of a dominant negative SK subunit [7], we now understand that the SK channels

Model 2: SK channels in pacemaker activity and synaptic response

Dopaminergic neurons (DA) of the ventral midbrain are important in the perception of reward, in motivational behavior and in the reinforcing actions of addictive drugs [19]. Impaired function of DA neurons is associated with the etiology of Parkinson's disease and schizophrenia [20, 21]. SK channels participate in determining the firing pattern of DA neurons, both as an intrinsic cell characteristic and in response to synaptic input.

DA cells in the adult exhibit intrinsic slow regular spiking [

Model 3: SK channels enable rapid firing and mode switching

Cerebellar Purkinje neurons provide the only output from the cerebellar cortex to the deep cerebellar nuclei. The firing rates of Purkinje neurons are thought to encode timing information for motor coordination and balance [34]. In brain slice recordings from adult rats and mice, Purkinje neurons predominantly display a tonic rhythmic firing pattern that occasionally transitions into bursting periods and long silent intervals. This trimodal firing pattern is an intrinsic property of the cells,

Model 4: converting an excitatory neurotransmitter signal into inhibition

Auditory outer hair cells (OHC) receive synaptic input from the superior olivary nucleus that elicits an inhibitory postsynaptic response (IPSP) and modulates cochlear afferent signals [42]. In contrast to most central inhibitory synapses, the OHC IPSPs are due to activation of acetylcholine (ACh) receptors that are usually excitatory [43, 44]. In these cells, the ACh receptors contain the α-9ACh subunit that endows Ca2+ permeability to the receptor [44]. The influx of Ca2+ activates SK2

Modulation

One theme that emerges from these studies is that SK channel activity, whether induced or tonic, is not all-or-none, leaving a window of opportunity for regulation. Because the channels are so steeply dependent upon the intracellular Ca2+ concentration, subtle changes in their Ca2+ response might have profound physiological consequences. The serine–threonine protein kinase CK2 is a stably bound component of the SK channel complex in the brain [52••]. SK-associated CK2 phosphorylates SK-bound

Conclusions

Recent work has led to new insights into the functional diversity and broad cellular and behavioral consequences of SK channel activity. Different cell types employ specific subsets of Ca2+ sources to dictate when, where and how fast the SK channel influence on membrane potential will be exerted. The absolute Ca2+ concentration change required and the extent of SK channel activity is also influenced by the phosphorylation state of SK-bound CaM, which, in turn, might reflect the recent activity

Update

Two groups have now shown that NMDA receptors and SK channels form a Ca2+-mediated feedback loop in dendritic spines [53, 54]. In CA1 pyramidal neurons and in the lateral amygdala, synaptically evoked Ca2+ influx that is blocked by blockers of NMDA receptors activates SK channels that provide a repolarizing shunt on the spine membrane potential. This favors Mg2+ re-block of NMDA receptors and influences the induction of synaptic plasticity.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank L Vaskalis for expert graphics assistance, and patience. We also thank all of our colleagues in this exciting field for their enthusiasm and interactions. We are supported by grants from the National Institutes of Health.

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