Neurophysiological process - Kappa-type opioid receptor in transmission of nerve impulses

Kappa-type opioid receptor in transmission of nerve impulses

Kappa-type opioid receptor belongs to the family of guanine nucleotide binding protein (G-protein) coupled receptors (GPCRs). Dynorphin A extracellular region is one of endogenous kappa-opioids [1]

Ligand binding to Kappa-type opioid receptor leads to dissociation of trimeric G-protein complex coupled with this receptor. Dissociation of trimeric G-protein complex results in release of activated G-protein alpha-i family and G-protein beta/gamma subunits. Released G-protein beta/gamma subunits bind to and inactivate P/Q-type calcium channel alpha-1A subunit and N-type Ca(II) channel alpha1B that contribute to voltage-dependent inward Ca2+ current. L-type Ca(II) channel, alpha 1C subunit also assists in this type of current and is inhibited by Kappa-type opioid receptor via an unknown mechanism [2], [3].

Besides inhibiting Ca2+ currents, G-protein beta/gamma activates inwardly rectifying K+ currents by directly binding GIRK: Kir3.1) [4], Kir3.2 [5] and Kir3.4 [6]. Inhibition of the high-voltage activated Ca2+ current and activation of the rectifying K+ current leads to decreased cell excitability and therefore to inhibition of nociceptive transmission (see regulation of sensory perception of pain).[7] L-type Ca(II) channel, alpha 1C subunit and Kir3.2 play role in Kappa-type opioid receptor mediated hypothermia [8], [9].

Modulation of pain transmission (see regulation of sensory perception of pain) can be achieved through attenuation of Dynorphin levels [10]. Dynorphin transcription is positively regulated by AP-1 and CREB1 transcription factors and repressed by DREAM [11], [12]. DREAM represses Dynorphin transcription through direct binding to DRE site of prodynorphin gene and through inhibition of CREB1 activity [13]. Both binding of Ca2+ ions to DREAM and CREM (activators)- DREAM interaction mediate derepression of Dynorphin expression [14], [15]. CREM (activators) - DREAM interaction does not require CREM (activators) phosphorylation by PKA-cat (cAMP-dependent) but is strengthened by such phosphorylation [14].

Kappa-type opioid receptor directly interacts with EBP50 and sequesters it from inhibiting NHE3 and therefore activates Na+/H+ exchange [16]. NHE3 is believed to play a key role in the acid-induced modulation of axons and Schwann cells [17].

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References:

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    kappa Opioid receptor interacts with Na(+)/H(+)-exchanger regulatory factor-1/Ezrin-radixin-moesin-binding phosphoprotein-50 (NHERF-1/EBP50) to stimulate Na(+)/H(+) exchange independent of G(i)/G(o) proteins. The Journal of biological chemistry 2004 Jun 11;279(24):25002-9
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    Distribution of pH regulators in the rat laryngeal nerve: the spatial relationship between Na(+)/HCO(3)(-) cotransporters and Na(+)/H(+) exchanger type 3. Neuroscience letters 2004 Sep 23;368(2):127-9