In experiments on isolated rat Purkinje neurons using the whole-cell patch-clamp technique, the addition of 10 nM of an agonist of μ-opioid receptors (μ-ORs), DAMGO, to the bath solution led to moderate but highly significant intensification of the current through high-threshold calcium channels of the P type (increment 9-10%). We found that this effect was independent of the kind of cations (Ca2+ or Ba2+) coming via the plasma membrane. This effect (positive modulation of the current) was practically preserved in the case where a prepulse shifting the membrane potential to +50 mV preceded the test pulse, i.e., the effect was voltage-independent. The above-mentioned effect was almost unchanged under conditions where the intracellular solution contained 0.5 mM GTPβS (an irreversible blocker of G-proteins) or the same amount of GTPγS (a nonspecific activator of these proteins) instead of GTP. The addition of 0.5 mM cAMP to the intracellular solution also did not practically influence positive modulation of the P-current under the action of DAMGO. Preliminary 10-min-long incubation of the examined cells in a solution containing 0.5 μM calmidazolium (an antagonist of calmodulin-regulated enzymes) induced a twofold decrease in the DAMGO-evoked increment of the P-current. Based on the obtained data, we hypothesize that there is a high-affinity allosteric site of binding with agonists of μ-ORs in the molecule of the calcium P-channel, and that voltage-, calcium-, and G-protein-independent positive modulation of the current through these channels is realized by just such a mechanism.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
P. Kostyuk, Calcium ions in nerve cell function, Oxford Neuroscience Series, Vol. 1, Oxford University Press, Oxford (1992).
C. J. Kim, J. S. Rhee, and N. Akaike, “Modulation of high-voltage activated Ca2+ channels in the rat periaqueductal gray neurons by mu-type opioid agonist,” J. Neurophysiol., 77, No. 3, 1418-1424 (1997).
F. A. Abdulla and P. A. Smith, “Nociceptin inhibits T-type Ca2+ channel current in rat sensory neurons by a G-protein-independent mechanism,” J. Neurosci., 17, No. 22, 8721-8728 (1997).
C. T. Tamse, Y. Xu, H. Song, et al., “Protein kinase A mediates voltage-dependent facilitation of Ca2+ current in presynaptic hair cells in Hermissenda ceassicornis,” J. Neurophysiol., 89, No. 3, 1718-1726 (2003).
F. Fournier, P. Charnet, E. Bourinet, et al., “Regulation by protein kinase-C of putative P-type Ca channels expressed in Xenopus oocytes from cerebellar mRNA,” FEBS Lett., 317, Nos. 1-2, 118-124 (1993).
O. V. Egorova, O. I. Fisyunov, and O. A. Kryshtal, “Effects of agonists of μ-opioid receptors on P-type calcium channels in rat Purkinje neurons,” Neurophysiology, 47, No. 2, 102-107 (2015).
I. M. Mintz, V. J. Venema, K. M. Swiderek, et al., “P-type calcium channels blocked by the spider toxin w-Aga-IVA,” Nature, 355, No. 6363, 827-829 (1992).
A. D. Corbett, G. Henderson, A. T. McKnight, et al., “75 years of opioid research: the exciting but vain quest for the Holy Grail,” Br. J. Pharmacol., 147, Suppl 1, S153-162 (2006).
S. Herlitze, D. E. Garcia, K. Mackie, et al., “Modulation of Ca2+ channels by G-protein beta gamma subunits,” Nature, 380, No. 6571, 258-262 (1996).
S. Kaneko, A. Akaike, and M. Satoh, “Receptormediated modulation of voltage-dependent Ca2+ channels via heterotrimeric G-proteins in neurons,” Jpn. J. Pharmacol., 81, No. 4, 324-331 (1999).
A. C. Dolphin, “Mechanisms of modulation of voltagedependent calcium channels by G proteins,” J. Physiol., 506, Pt. 1, 3-11 (1998).
R. Al-Hasani and M. R. Bruchas, “Molecular mechanisms of opioid receptor-dependent signaling and behavior,” Anesthesiology, 115, No. 6, 1363-1381 (2011).
D. Wang, W. Sadee, and J. M. Quillan, “Calmodulin binding to G protein-coupling domain of opioid receptors,” J. Biol. Chem., 274, No. 31, 22081-22088 (1999).
A. Lee, S. T. Wong, D. Gallagher, et al., “Ca2+/calmodulin binds to and modulates P/Q-type calcium channels,” Nature, 399, No. 6732, 155-159 (1999).
A. I. Fisyunov, N. A. Lozovaya, T. S. Tsyntsadze, et al., “Modulating action of hyperforin on the P-type calcium channels in the membranes of rat cerebellar Purkinje neurons,” Neurophysiology, 33, No. 1, 5-10 (2001).
L. G. Wu, R. E. Westenbroek, J. G. Borst, et al., “Calcium channel types with distinct presynaptic localization couple differentially to transmitter release in single calyx-type synapses,” J. Neurosci., 19, No. 2, 726-736 (1999).
R. W. Tsien and R. Y. Tsien, “Calcium channels, stores, and oscillations,” Annu. Rev. Cell Biol., 6, 715-760 (1990).
H. Bito, K. Deisseroth, and R. W. Tsien, “Ca2+-dependent regulation in neuronal gene expression,” Curr. Opin. Neurobiol., 7, No. 3, 419-429 (1997).
M. Minami and M. Satoh, “Molecular biology of the opioid receptors: structures, functions and distributions,” Neurosci. Res., 23, No. 2, 121-145 (1995).
O. Keren, M. Gafni, and Y. Sarne, “Opioids potentiate transmitter release from SK-N-SH human neuroblastoma cells by modulating N-type calcium channels,” Brain Res., 764, Nos. 1-2, 277-282 (1997).
O. Keren, M. Gafni, and Y. Sarne, “Potentiation of transmitter release from NMB human neuroblastoma cells by kappa-opioids is mediated by N-type voltagedependent calcium channels,” Brain Res., 843, Nos. 1-2, 193-198 (1999).
W. A. Twitchell and S. G. Rane, “Nucleotide-independent modulation of Ca2+-dependent K+ channel current by a mu-type opioid receptor,” Mol. Pharmacol., 46, No. 5, 793-798 (1994).
P. James, T. Vorherr, and E. Carafoli, “Calmodulinbinding domains: just two faced or multi-faceted?,” Trends Biochem. Sci., 20, No. 1, 38-42 (1995).
M. Sunagawa, H. Yokoshiki, T. Seki, et al., “Direct block of Ca2+ channels by calmidazolium in cultured vascular smooth muscle cells,” J. Cardiovasc. Pharmacol., 34, No. 4, 488-496 (1999).
J. A. Brzostowski and A. R. Kimmel, “Signaling at zero G: G-protein-independent functions for 7-TM receptors,” Trends Biochem. Sci., 26, No. 5, 291-297 (2001).
R. A. Hall and R. J. Lefkowitz, “Regulation of G proteincoupled receptor signaling by scaffold proteins,” Circ. Res., 91, No. 8, 672-680 (2002).
D. A. Doyle, A. Lee, J. Lewis, et al., “Crystal structures of a complexed and peptide-free membrane proteinbinding domain: molecular basis of peptide recognition by PDZ,” Cell, 85, No.7, 1067-1076 (1996).
P. Huang, D. Steplock, E. J. Weinman, et al., “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,” J. Biol. Chem., 279, No. 24, 25002-25009 (2004).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Egorova, O.V., Fisyunov, O.I., Maksymyuk, O.P. et al. Mechanisms Underlying Positive Modulation of a Current through P-Type Calcium Channels in Purkinje Neurons by an Agonist of Opioid Receptors. Neurophysiology 48, 230–237 (2016). https://doi.org/10.1007/s11062-016-9593-7
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11062-016-9593-7