Voltage Sensitive Calcium Channels

Voltage-sensitive calcium channels (VSCC) are activated during depolarization and allow the influx of calcium, thereby contributing to depolarization. The current flux generated by the movement of this divalent ion is relatively small compared to sodium and potassium currents. However, calcium is not only a charge carrier; it also functions as a second messenger within cells, opening calcium-dependent ion channels, triggering neurotransmitter release in presynaptic terminals and activating calcium-dependent enzymes within the cytosol. Ten molecularly distinct pore-forming calcium channel subunits have been described (96). Based on electrophysiological properties, these can be differentiated into high- or low-threshold VSCC, both of which can be found in visceral sensory neurons. The high-threshold VSCC can be separated into L, N, P/Q, and R type currents based on their pharmacological properties. The N and P/Q type calcium currents are blocked by ra-conotoxin GIVA and ra-agatoxin, respectively. Both toxins significantly inhibit synaptic transmission within the spinal cord

Figure 6 Potassium currents in visceral inflammation. (A) Superimposed current tracings triggered by stepwise depolarization of a gastric dorsal root ganglion neuron show transient and sustained potassium currents. (B) Ulceration decreases the transient current in gastric nodose and dorsal root ganglion neurons. Abbreviations: NG, nodose ganglion; DRG, dorsal root ganglion.

demonstrating the importance of these channels in transmitter release (97). Genetic deletion or pharmacologic inhibition of VSCC blunts pain responses in experimental animals, which is at least in part due to the decreased transmitter release within the spinal cord (98-101). Conversely, hypersensitivity induced by gastric inflammation is associated with a shift in the voltage-dependence of activation to less depolarized potentials, which may enhance transmitter release and contribute to the development of visceral hypersensitivity (Fig. 7).

Activation of opioid receptors on primary afferent neurons inhibits VSCC and may thus modulate transmitter release (102,103). Initial results point at differences between cutaneous and visceral afferents with k- rather than m- or 8-opioid agonists primarily affecting VSCC in colon sensory neurons (104). Considering the possible use of peripherally acting agents without the typical adverse effects of traditional opioids, these findings may open up important therapeutic options.

VSCC are comprised of different proteins that form a multimeric complex, which—in the case of high-threshold VSCC—includes the pore-forming a subunit, an intracellular P subunit, and a large a2d subunit. The interactions between these proteins are functionally very important as illustrated by the genetic deletion of the P3 subunit, which alters the voltage-dependence of calcium currents in dorsal root ganglion neurons and blunts responses to inflammatory pain (105). Nerve injury is associated with an increase in the expression of this a2d subunit (106). Interestingly, this subunit binds the anticonvulsive agent gabapentin, which inhibits VSCC (107). This effect may underlie the finding that gabapentin can improve neuropathic pain and may be beneficial in the treatment of visceral hyperalgesia (108-110).

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