Ca²⁺ Feedback Via SK Channels

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Calcium ions are powerful metabolic regulators, coordinating almost all intracellular pathways. In some cases, these ions act as on-off switches, but their usual mode is to function as rheostats, adjusting and fine-tuning integrated processes by modulating multiple intracellular components. The importance of this modulation is reflected by the extremely tight control maintained over free Ca²⁺ levels, [Ca²⁺]_i.

Because ion channels that determine the electrical characteristics of neurons have evolved Ca²⁺-sensing abilities, changes in [Ca²⁺]_i can affect the membrane potential. A principal example is a class of K+ channels, SK channels, that open and close in response to the rise and fall of [Ca²⁺]_i. This is accomplished by a unique, constitutive interaction between the channel protein and the prototypic Ca²⁺ sensor, calmodulin. Therefore, as Ca²⁺ ions enter the neuron, for example through the voltage-dependent Ca²⁺ channels that open during an action potential, SK channels open, inducing a hyperpolarizing influence and dampening excitability. The SK-mediated hyperpolarization, in turn, closes the voltage-dependent Ca²⁺ channels and limits Ca²⁺ influx.

Cellular events that underlie learning and memory are reflected by activity-dependent changes in synaptic strength, called synaptic plasticity. One well developed model for synaptic plasticity is based on the connection between presynaptic CA3 and postsynaptic CA1 neurons in the hippocampus. At these synapses, glutamate released from the presynaptic terminals binds to AMPA and NMDA-types of ionotropic glutamate receptors on the postsynaptic dendritic spine. Activation of AMPA receptors depolarizes the spine membrane and the coincident signal, glutamate binding and depolarization (which relieves the voltage-dependent block by external Mg²⁺), opens the NMDA receptors. The crucial determinant inducing synaptic plasticity is the amount of Ca²⁺ that enters through the NMDA receptor channels. The Adelman lab recently found that blocking SK channels in these cells increased synaptic plasticity. In parallel, acquisition of hippocampal-dependent tasks was facilitated in mice given SK channel blockers. Using synaptic stimulations together with recordings from CA1 neurons, the lab showed that a population of SK channels is positioned strategically within the small space of the dendritic spine, close to NMDA receptors, where the two channel types form a spine-specific Ca²⁺ feedback loop. Ca²⁺ entering through the NMDA receptors opens the neighboring SK channels. The SK-mediated repolarization favors external Mg²⁺ block of the NMDA receptors and limits Ca²⁺ influx. In collaboration with Dr. Bernardo Sabatini at Harvard, the lab used two-photon microscopy to show that blocking the spine SK channels increased the amount of Ca²⁺ entering through the NMDA receptors. Taken together, the results reveal a novel role for SK channels in modulating the induction of synaptic plasticity. This modulation has important implications for models of learning and memory.

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