IKCa Channels Are a Critical Determinant of the Slow AHP in CA1 Pyramidal Neurons

Abstract

Control over the frequency and pattern of neuronal spike discharge depends on Ca2+-gated K+ channels that reduce cell excitability by hyperpolarizing the membrane potential. The Ca2+-dependent slow afterhyperpolarization (sAHP) is one of the most prominent inhibitory responses in the brain, with sAHP amplitude linked to a host of circuit and behavioral functions, yet the channel that underlies the sAHP has defied identification for decades. Here, we show that intermediate-conductance Ca2+-dependent K+ (IKCa) channels underlie the sAHP generated by trains of synaptic input or postsynaptic stimuli in CA1 hippocampal pyramidal cells. These findings are significant in providing a molecular identity for the sAHP of central neurons that will identify pharmacological tools capable of potentially modifying the several behavioral or disease states associated with the sAHP.

The potassium channel KCa3.1 constitutes a pharmacological target for neuroinflammation associated with ischemia/reperfusion stroke

“…A recent publication suggested that KCa3.1 might be involved in the slow afterhyperpolarization in hippocampal neurons. 31 However, if there is any similarity between the roles of the fast (KCa1.1 ¼ BK), medium (KCa2 ¼ SK) and slow afterhyperpolarization (KCa3.1 ¼ IK) in terms of neuroprotection, then it would be highly unlikely that KCa3.1 inhibition would be neuroprotective by inhibiting the sAHP. Typically, compounds that enhance the AHP are neuroprotective, while blockers rather have the opposite effect.…”

International Union of Basic and Clinical Pharmacology. C. Nomenclature and Properties of Calcium-Activated and Sodium-Activated Potassium Channels

“…In all these tissues, K Ca 3.1 regulates Ca 2+ signaling and membrane potential. Although two recent studies indicated that K Ca 3.1 may be expressed in neurons and that it may contribute to the slow afterhyperpolarization that follows a burst of action potentials in neurons of the hippocampus (King et al, 2015;Turner et al, 2015), another study presented data that K Ca 3.1 does not contribute to this slow AHP (Wang et al, 2016). The potential role of the channel in neurons therefore currently remains unclear.…”

Evidence of Decreased Activity in Intermediate-Conductance Calcium-Activated Potassium Channels During Retinoic Acid–Induced Differentiation in Motor Neuron–Like NSC-34 Cells

“…However, the observed magnitude of TRAM-34-sensitive I K in undifferentiated cells was considerably higher than that in RA-differentiated cells. Thus, as NSC-34 cells continue to differentiate with RA, the resultant decrease in the amplitude of TRAM-34-sensitive I K due to the decreased activity of IK Ca channels may not only produce a progressive reduction of K + efflux and depolarize the cell but also may result in the suppression of after-hyperpolarizing potentials [11,14]. Such maintained membrane depolarization accompanied by an increase in neuronal excitability would be prepared to elicit voltage-gated Na + or Ca 2+ currents in response to depolarizing inputs, thereby inducing regenerative neuronal firing [13,26].…”

“…However, the modulators of functional IK Ca channels have been demonstrated to perturb the functional activities of central neurons including motor neurons [8][9][10][11][12][13]. More specifically, the activity of these channels increases as voltage-gated Ca 2+ channels are facilitated by overactivity or neuron recovery (e.g., motor neuron recovery) during spinal cord injuries [8][9][10][11]. K Ca 3.1 channels appear to be strongly linked to a phenotype of hyperactivity disorder, at least in mice [13].…”