Presynaptic Ca²⁺-Activated K⁺Channels in Glutamatergic Hippocampal Terminals and Their Role in Spike Repolarization and Regulation of Transmitter Release

Abstract

Large-conductance Ca 2ϩ -activated K ϩ channels (BK, also called Maxi-K or Slo channels) are widespread in the vertebrate nervous system, but their functional roles in synaptic transmission in the mammalian brain are largely unknown. By combining electrophysiology and immunogold cytochemistry, we demonstrate the existence of functional BK channels in presynaptic terminals in the hippocampus and compare their functional roles in somata and terminals of CA3 pyramidal cells. Doublelabeling immunogold analysis with BK channel and glutamate receptor antibodies indicated that BK channels are targeted to the presynaptic membrane facing the synaptic cleft in terminals of Schaffer collaterals in stratum radiatum. Whole-cell, intracellular, and field-potential recordings from CA1 pyramidal cells showed that the presynaptic BK channels are activated by calcium influx and can contribute to repolarization of the presynaptic action potential (AP) and negative feedback control of Ca 2ϩ influx and transmitter release. This was observed in the presence of 4-aminopyridine (4-AP, 40-100 M), which broadened the presynaptic compound action potential. In contrast, the presynaptic BK channels did not contribute significantly to regulation of action potentials or transmitter release under basal experimental conditions, i.e., without 4-AP, even at high stimulation frequencies. This is unlike the situation in the parent cell bodies (CA3 pyramidal cells), where BK channels contribute strongly to action potential repolarization. These results indicate that the functional role of BK channels depends on their subcellular localization.

Opposing effects of spinal nerve ligation on calcium-activated potassium currents in axotomized and adjacent mammalian primary afferent neurons

“…Current through these channels contributes to the early AHP, prolongs the refractory period, and limits repetitive firing. Additionally, BK current shortens AP duration by accelerating repolarization, thereby limiting the amount of Ca 2+ influx during an AP and thereby decreasing neurotransmitter release [38,72,75]. Our methods characterizing I K(Ca) in sensory neurons adds validity to these previous findings by using methods that employ a natural AP waveform stimulus in one case, and by controlling cytoplasmic Ca 2+ levels in the other.…”

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

“…BK channels are positioned to react to action potential-triggered Ca 2+ influx. Electrophysiological approaches indicate that BK channels can control glutamate release under conditions of excessive neuronal activity (Gribkoff et al, 2001a;Hu et al, 2001;Yamashita et al, 2006). Functionally, a deficit in axonal or presynaptic BK channels might render mossy fibers hyperexcitable during epileptogenesis.…”

“…The precise distribution and preferential trafficking of BK channels to axon terminals and somatodendritic regions can ultimately determine the function of BK channels in neurons and circuits. For instance, in hippocampal pyramidal neurons, BK channels are trafficked to presynaptic membranes where they are thought to modulate glutamatergic neurotransmission in conditions of excessive excitability (Hu et al, 2001). Nevertheless, in many neurons, BK channels also contribute to the action potential repolarization and to the fast afterhyperpolarization thereby influence additionally the neuronal firing frequency (Shao et al, 1999).…”

“…The abundance of BK channels on such subcellular locations is differentially regulated across several neuronal phenotypes. In the hippocampus, for instance, BK channels are highly expressed at the Schaffer's collateral pathway and mossy fibers of granule cells (Hu et al, 2001;Knaus et al, 1996;Misonou et al, 2006;Sailer et al, 2006).…”

Regional Differences in Distribution and Functional Expression of Small-Conductance Ca2+-Activated K+Channels in Rat Brain

“…cAMP analogues [in M: 100 cAMP or 100 8 chlorophenylthio (CPT)-cAMP] in the intracellular medium in the recording pipette (Madison and Nicoll, 1986). The SK channels are known to be predominately resistant to these drug concentrations (Ishii et al, 1997;Wang et al, 1998;Hu et al, 2001), but evidence for a small cAMP-induced increase of I aAHP has been reported (Stocker and Pedarzani, 2000). The blockade of non-SK K ϩ channels also served to increase the cell input resistance, thereby facilitating the activation of voltage-gated Ca 2ϩ channels and, hence, Ca 2ϩ influx and SK channel activation and improving the space clamp of the cell.…”