BK potassium channels control transmitter release at CA3–CA3 synapses in the rat hippocampus

Abstract

Large conductance calcium-and voltage-activated potassium channels (BK channels) activate in response to calcium influx during action potentials and contribute to the spike repolarization and fast afterhyperpolarization. BK channels targeted to active zones in presynaptic nerve terminals have been shown to limit calcium entry and transmitter release by reducing the duration of the presynaptic spike at neurosecretory nerve terminals and at the frog neuromuscular junction. However, their functional role in central synapses is still uncertain. In the hippocampus, BK channels have been proposed to act as an 'emergency brake' that would control transmitter release only under conditions of excessive depolarization and accumulation of intracellular calcium. Here we demonstrate that in the CA3 region of hippocampal slice cultures, under basal experimental conditions, the selective BK channel blockers paxilline (10 µM) and iberiotoxin (100 nM) increase the frequency, but not the amplitude, of spontaneously occurring action potential-dependent EPSCs. These drugs did not affect miniature currents recorded in the presence of tetrodotoxin, suggesting that their action was dependent on action potential firing. Moreover, in double patch-clamp recordings from monosynaptically interconnected CA3 pyramidal neurones, blockade of BK channels enhanced the probability of transmitter release, as revealed by the increase in success rate, EPSC amplitude and the concomitant decrease in paired-pulse ratio in response to pairs of presynaptic action potentials delivered at a frequency of 0.05 Hz. BK channel blockers also enhanced the appearance of delayed responses, particularly following the second action potential in the paired-pulse protocol. These results are consistent with the hypothesis that BK channels are powerful modulators of transmitter release and synaptic efficacy in central neurones.

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

“…Spontaneous firing develops also in injured myelinated afferents after SNL [53], thus our findings that axotomized myelinated -but not adjacent uninjured afferents-develop increased excitability, and axotomized medium-sized fibers lose I K(Ca) , contribute additional support to the argument that injured (and not uninjured) myelinated afferents mediate neuropathic pain behavior after SNL [6]. Because BK channels control neurotransmitter release [86] and inter-neuronal glutaminergic synaptic efficacy [72], it is also likely that loss of BK currents in small and medium sized neurons after axotomy may enhance synaptic transmission of afferent signaling, as well. In addition to loss of I K(Ca) currents in a manner directly related to nerve injury, we have also previously shown that neuropathy decreases I Ca [60,61], a mechanism that may reduce the activation of K (Ca) currents in addition to the direct effect of SNL, thus leading to a higher enhancement of excitability.…”

“…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.…”

Genetic activation of BK currents in vivo generates bidirectional effects on neuronal excitability

“…BK channels are widely expressed in excitable and nonexcitable cells (4), suggesting that they are highly versatile players in membrane signaling. In neurons and muscle, BK currents are activated by simultaneous membrane depolarization and an increase in intracellular Ca 2+ (Ca 2+ i ) (1,5), shaping the falling phase of the action potential, the afterhyperpolarization (AHP), and some Ca 2+ transients that underlie neurotransmitter release and secretion (6)(7)(8)(9). Deletion of Kcnma1 leads to a constellation of defects related to hyperexcitability (2,10).…”

Profiling the Phospho-status of the BKCa Channel α Subunit in Rat Brain Reveals Unexpected Patterns and Complexity

“…In mammalian central neurons, BK Ca channels underlie the repolarization and fast after-hyperpolarization of action potentials (13,14), shape dendritic Ca 2ϩ spikes (15), and control neurotransmitter release at presynaptic terminals (16,17). BK Ca channels also play key roles in other diverse physiological processes such as contractile tone of various types of smooth muscle cells, frequency tuning of auditory hair cells, hormone secretion, and innate immunity (9 -11).…”