Calcium regulation of a slow post-spike hyperpolarization in vagal afferent neurons

Abstract

Activation of distinct classes of potassium channels can dramatically affect the frequency and the pattern of neuronal firing. In a subpopulation of vagal afferent neurons (nodose ganglion neurons), the pattern of impulse activity is effectively modulated by a Ca 2؉ -dependent K ؉ current. This current produces a post-spike hyperpolarization (AHP slow ) that plays a critical role in the regulation of membrane excitability and is responsible for spike-frequency accommodation in these neurons. Inhibition of the AHP slow by a number of endogenous autacoids (e.g., histamine, serotonin, prostanoids, and bradykinin) results in an increase in the firing frequency of vagal afferent neurons from <0.1 to >10 Hz. After a single action potential, the AHP slow in nodose neurons displays a slow rise time to peak (0.3-0.5 s) and a long duration (3-15 s Activation and sensitization of primary afferent nerve fibers during allergic inflammation are orchestrated by inflammatory mediators released from various cells, including tissue mast cells. Inf lammatory mediators provoke excitability changes in sensory nerves through diverse mechanisms, including (i) modification of the density and coupling efficacy of ligand-gated ionic channels; (ii) alteration in voltage-gated sodium, potassium, and calcium channels; and (iii) manipulation of cellular mechanisms that control spike-frequency adaptation.After immunologic activation of mast cells in airway in vivo or in sensory ganglia in vitro, a wide range of electrophysiological changes can be detected in peripheral sensory nerve terminals of the vagus (1) and in vagal primary afferent somata (located in the nodose and jugular ganglia) (2). These changes range from transient (minutes) membrane depolarizations that sometimes reach action potential (AP) threshold (3) to a sustained (days) unmasking of functional NK-2 tachykinin receptors (4, 5). One electrical membrane property that is particularly sensitive to inflammatory mediators is a slow post-spike afterhyperpolarization (AHP slow ; see Fig. 1 ) (3).This slow afterpotential influences neuronal excitability and determines the frequency and pattern of neuronal discharge. We have found that the amplitude and duration of the AHP slow are exquisitely sensitive to known inflammatory mediators such as prostanoids, amines, and kinins applied exogenously (Table 1) or released endogenously (i.e., after immunologic activation of mast cells) (3, 6). Inhibition of the AHP slow is accompanied by a loss of spike-frequency adaptation. Thus, modulation of the AHP slow amplitude and duration provides a mechanism for neuronal sensitization.We are interested in identifying the ionic channels and second-messenger transduction pathways that participate in the initiation and maintenance of the AHP slow in vagal primary afferent neurons. In this report, we describe the general properties of this slow afterpotential and our progress in its characterization. Our working hypothesis is that a close functional proximity between three separate channels [N t...

A Functional Role for Small-Conductance Calcium-Activated Potassium Channels in Sensory Pathways Including Nociceptive Processes

“…Although these reports provide firm evidence for calcium-activated potassium conductances in sensory afferents, the relationship between these native channels and the cloned SK channels is not entirely clear. The nodose AHP channels are not blocked by apamin (Cordoba-Rodriguez et al, 1999), whereas a very high (1 M) concentration of apamin was used to block the slow AHP in rat neurons (Gold et al, 1996). Furthermore, many of the properties of these slow AHPs, such as their regulation and their slow kinetics, are similar to those of the slow afterhyperpolarizations found in hippocampal pyramidal neurons.…”

“…For example, in guinea pig and rabbit nodose afferents, calcium influx and calcium-induced calcium release activate potassium-selective channels that generate a slow postspike afterhyperpolarization. This AHP is abolished by inflammatory mediators, causing an increase in neuronal excitability and a reduction in spike frequency adaptation (Fowler et al, 1985;Cordoba-Rodriguez et al, 1999). Gold et al (1996) reported a similarly slow, Ca 2ϩ -dependent afterhyperpolarization, regulated by prostaglandins, in cultured rat DRG neurons.…”

Role of prostaglandin D2 in mast cell activation-induced sensitization of esophageal vagal afferents

“…In cultured DRG neurons, PGD 2 evoked an accumulation of cAMP (25) and increased the amplitude of TTX-resistant Na ϩ currents via the DP 1 receptor (7). In nodose neurons, PGD 2 inhibited postspike hyperpolarization, resulting in an increase in the firing frequency (5). Extracellular recording of direct-current potentials indicated that PGD 2 perfusion caused a depolarization response of vagal C fibers (25).…”

Activation of Protein Kinase C in Sensory Neurons Accelerates Ca2+Uptake into the Endoplasmic Reticulum

“…An increased rate of [Ca 2ϩ ] i recovery reduces prominent Ca 2ϩ -activated K ϩ currents in DRG neurons (Sah, 1996). The resulting attenuation of the slow afterhyperpolarization in these cells is predicted to reduce spike frequency adaptation and to increase excitability (Abdulla and Smith, 1997;Cordoba-Rodriguez et al, 1999;Bahia et al, 2005). The shape of the presynaptic [Ca 2ϩ ] i transient has profound effects on neurotransmitter release as does the level of residual Ca 2ϩ (Kamiya and Zucker, 1994;Chen and Regehr, 1999;Muschol and Salzberg, 2000;Korogod et al, 2005).…”