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

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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].



Objects list:

AP-1 AP-1 Group of complexes
CREB1 Cyclic AMP-responsive element-binding protein 1
CREM (activators) cAMP-responsive element modulator
DREAM Calsenilin
Dynorphin Proenkephalin-B
Dynorphin A extracellular region Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys Peptide
EBP50 Na(+)/H(+) exchange regulatory cofactor NHE-RF1
G-protein alpha-i family G-protein alpha-i family Protein group
G-protein beta/gamma G-protein beta/gamma Group of complexes
GIRK GIRK Complex
Kappa-type opioid receptor Kappa-type opioid receptor
Kir3.1 G protein-activated inward rectifier potassium channel 1
Kir3.2 G protein-activated inward rectifier potassium channel 2
Kir3.4 G protein-activated inward rectifier potassium channel 4
L-type Ca(II) channel, alpha 1C subunit Voltage-dependent L-type calcium channel subunit alpha-1C
N-type Ca(II) channel alpha1B Voltage-dependent N-type calcium channel subunit alpha-1B
NHE3 Sodium/hydrogen exchanger 3
P/Q-type calcium channel alpha-1A subunit Voltage-dependent P/Q-type calcium channel subunit alpha-1A
PKA-cat (cAMP-dependent) Protein kinase, cAMP-dependent, catalytic Protein group

References:

  1. Satoh M, Minami M
    Molecular pharmacology of the opioid receptors. Pharmacology & therapeutics 1995;68(3):343-64
  2. Kaneko S, Yada N, Fukuda K, Kikuwaka M, Akaike A, Satoh M
    Inhibition of Ca2+ channel current by mu- and kappa-opioid receptors coexpressed in Xenopus oocytes: desensitization dependence on Ca2+ channel alpha 1 subunits. British journal of pharmacology 1997 Jun;121(4):806-12
  3. Rusin KI, Giovannucci DR, Stuenkel EL, Moises HC
    Kappa-opioid receptor activation modulates Ca2+ currents and secretion in isolated neuroendocrine nerve terminals. The Journal of neuroscience : the official journal of the Society for Neuroscience 1997 Sep 1;17(17):6565-74
  4. Ikeda K, Kobayashi T, Ichikawa T, Usui H, Kumanishi T
    Functional couplings of the delta- and the kappa-opioid receptors with the G-protein-activated K+ channel. Biochemical and biophysical research communications 1995 Mar 8;208(1):302-8
  5. Ulens C, Daenens P, Tytgat J
    The dual modulation of GIRK1/GIRK2 channels by opioid receptor ligands. European journal of pharmacology 1999 Dec 3;385(2-3):239-45
  6. Matthes H, Seward EP, Kieffer B, North RA
    Functional selectivity of orphanin FQ for its receptor coexpressed with potassium channel subunits in Xenopus laevis oocytes. Molecular pharmacology 1996 Sep;50(3):447-50
  7. Ikeda K, Kobayashi T, Kumanishi T, Yano R, Sora I, Niki H
    Molecular mechanisms of analgesia induced by opioids and ethanol: is the GIRK channel one of the keys? Neuroscience research 2002 Oct;44(2):121-131
  8. Gullapalli S, Ramarao P
    Role of L-type Ca(2+) channels in pertussis toxin induced antagonism of U50,488H analgesia and hypothermia. Brain research 2002 Aug 16;946(2):191-7
  9. Costa AC, Stasko MR, Stoffel M, Scott-McKean JJ
    G-protein-gated potassium (GIRK) channels containing the GIRK2 subunit are control hubs for pharmacologically induced hypothermic responses. The Journal of neuroscience : the official journal of the Society for Neuroscience 2005 Aug 24;25(34):7801-4
  10. Sours-Brothers S, Ma R, Koulen P
    Ca2+-sensitive transcriptional regulation: direct DNA interaction by DREAM. Frontiers in bioscience : a journal and virtual library 2009 Jan 1;14:1851-6
  11. Cole RL, Konradi C, Douglass J, Hyman SE
    Neuronal adaptation to amphetamine and dopamine: molecular mechanisms of prodynorphin gene regulation in rat striatum. Neuron 1995 Apr;14(4):813-23
  12. Collins-Hicok J, Lin L, Spiro C, Laybourn PJ, Tschumper R, Rapacz B, McMurray CT
    Induction of the rat prodynorphin gene through Gs-coupled receptors may involve phosphorylation-dependent derepression and activation. Molecular and cellular biology 1994 May;14(5):2837-48
  13. Müller D
    [Determination of F-wave conductivity in the normal N. ulnaris]. Psychiatrie, Neurologie, und medizinische Psychologie 1975 Oct;27(10):619-23
  14. Ledo F, Carrión AM, Link WA, Mellström B, Naranjo JR
    DREAM-alphaCREM interaction via leucine-charged domains derepresses downstream regulatory element-dependent transcription. Molecular and cellular biology 2000 Dec;20(24):9120-6
  15. Osawa M, Tong KI, Lilliehook C, Wasco W, Buxbaum JD, Cheng HY, Penninger JM, Ikura M, Ames JB
    Calcium-regulated DNA binding and oligomerization of the neuronal calcium-sensing protein, calsenilin/DREAM/KChIP3. The Journal of biological chemistry 2001 Nov 2;276(44):41005-13
  16. Huang P, Steplock D, Weinman EJ, Hall RA, Ding Z, Li J, Wang Y, Liu-Chen LY
    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
  17. Yamamoto Y, Taniguchi K
    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

  1. Satoh M, Minami M
    Molecular pharmacology of the opioid receptors. Pharmacology & therapeutics 1995;68(3):343-64
  2. Kaneko S, Yada N, Fukuda K, Kikuwaka M, Akaike A, Satoh M
    Inhibition of Ca2+ channel current by mu- and kappa-opioid receptors coexpressed in Xenopus oocytes: desensitization dependence on Ca2+ channel alpha 1 subunits. British journal of pharmacology 1997 Jun;121(4):806-12
  3. Rusin KI, Giovannucci DR, Stuenkel EL, Moises HC
    Kappa-opioid receptor activation modulates Ca2+ currents and secretion in isolated neuroendocrine nerve terminals. The Journal of neuroscience : the official journal of the Society for Neuroscience 1997 Sep 1;17(17):6565-74
  4. Ikeda K, Kobayashi T, Ichikawa T, Usui H, Kumanishi T
    Functional couplings of the delta- and the kappa-opioid receptors with the G-protein-activated K+ channel. Biochemical and biophysical research communications 1995 Mar 8;208(1):302-8
  5. Ulens C, Daenens P, Tytgat J
    The dual modulation of GIRK1/GIRK2 channels by opioid receptor ligands. European journal of pharmacology 1999 Dec 3;385(2-3):239-45
  6. Matthes H, Seward EP, Kieffer B, North RA
    Functional selectivity of orphanin FQ for its receptor coexpressed with potassium channel subunits in Xenopus laevis oocytes. Molecular pharmacology 1996 Sep;50(3):447-50
  7. Ikeda K, Kobayashi T, Kumanishi T, Yano R, Sora I, Niki H
    Molecular mechanisms of analgesia induced by opioids and ethanol: is the GIRK channel one of the keys? Neuroscience research 2002 Oct;44(2):121-131
  8. Gullapalli S, Ramarao P
    Role of L-type Ca(2+) channels in pertussis toxin induced antagonism of U50,488H analgesia and hypothermia. Brain research 2002 Aug 16;946(2):191-7
  9. Costa AC, Stasko MR, Stoffel M, Scott-McKean JJ
    G-protein-gated potassium (GIRK) channels containing the GIRK2 subunit are control hubs for pharmacologically induced hypothermic responses. The Journal of neuroscience : the official journal of the Society for Neuroscience 2005 Aug 24;25(34):7801-4
  10. Sours-Brothers S, Ma R, Koulen P
    Ca2+-sensitive transcriptional regulation: direct DNA interaction by DREAM. Frontiers in bioscience : a journal and virtual library 2009 Jan 1;14:1851-6
  11. Cole RL, Konradi C, Douglass J, Hyman SE
    Neuronal adaptation to amphetamine and dopamine: molecular mechanisms of prodynorphin gene regulation in rat striatum. Neuron 1995 Apr;14(4):813-23
  12. Collins-Hicok J, Lin L, Spiro C, Laybourn PJ, Tschumper R, Rapacz B, McMurray CT
    Induction of the rat prodynorphin gene through Gs-coupled receptors may involve phosphorylation-dependent derepression and activation. Molecular and cellular biology 1994 May;14(5):2837-48
  13. Müller D
    [Determination of F-wave conductivity in the normal N. ulnaris]. Psychiatrie, Neurologie, und medizinische Psychologie 1975 Oct;27(10):619-23
  14. Ledo F, Carrión AM, Link WA, Mellström B, Naranjo JR
    DREAM-alphaCREM interaction via leucine-charged domains derepresses downstream regulatory element-dependent transcription. Molecular and cellular biology 2000 Dec;20(24):9120-6
  15. Osawa M, Tong KI, Lilliehook C, Wasco W, Buxbaum JD, Cheng HY, Penninger JM, Ikura M, Ames JB
    Calcium-regulated DNA binding and oligomerization of the neuronal calcium-sensing protein, calsenilin/DREAM/KChIP3. The Journal of biological chemistry 2001 Nov 2;276(44):41005-13
  16. Huang P, Steplock D, Weinman EJ, Hall RA, Ding Z, Li J, Wang Y, Liu-Chen LY
    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
  17. Yamamoto Y, Taniguchi K
    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

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