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Regulation of Membrane Transporters by Delta-Opioid Receptors

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Neural Functions of the Delta-Opioid Receptor

Abstract

Neuronal excitability and synaptic transmissions are critical for both pain sensation and drug addiction. While the Na+, K+ ATPase contributes to maintaining the excitability of neurons, communications between neurons are mainly achieved by synaptic transmission via either glutamate or γ-aminobutyric acid (GABA), two main neurotransmitters that mediate excitatory postsynaptic potential (EPSP) and inhibitory postsynaptic potential (IPSP), respectively. Neurotransmitter transporters control the dwell time and concentration of the respective transmitters in the synaptic cleft; therefore, regulate dynamics of EPSP and IPSP. Opioid receptors are well known modulators in pain sensation and drug addiction, and are located abundantly in synaptic clefts as well. However, little is known whether and how opioid receptors interact regulatorily with Na+, K+ ATPase or neurotransmitter transporters. Here we review recent findings, which build the missing link between delta-opioid receptor (DOR) and glutamate/GABA transporters, and Na+, K+ ATPase. First, we show that excitatory amino-acid carrier 1 (EAAC1), a glutamate transporter, co-localizes with DOR; co-expression of DOR inhibits EAAC1 activity, and this inhibition is relieved by DOR activation. Second, we show that, similar to EAAC1, the activity of the major GABA transporter GAT1 is inhibited by DOR co-expression; but unlike EAAC1, activation of DOR further inhibits GAT1 activity. Third, similar to the findings with EAAC1 and GAT1, Na+, K+ pump activity is inhibited by co-expression with DOR, whereas DOR activation has no significant effect on Na+, K+ pump activity. On the other hand, pump stimulation reduces DOR sensitivity for the agonist. These studies provide novel regulatory roles of DOR in synaptic proteins that are essential in excitability, synaptic transmission, and synaptic plasticity, and shed light on how interactions between neurotransmitter transporters/Na+, K+ pumps and DOR may regulate analgesia and addictive drug use.

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Abbreviations

CNS:

Central nervous system

DAMGO:

[D Ala2,N-Me-Phe4,Gly5-ol]-enkephalin

DOR:

δ-Opioid receptor (delta-opioid receptor)

DPDPE:

[D-Pen2,5]-enkephalin

EAAC1:

Excitatory amino acid carrier 1

EPSP:

Excitatory postsynaptic potential

GABA:

Gamma-amino-butyric acid

GAT:

GABA transporter

IPSP:

Inhibitory postsynaptic potential

KOR:

κ-Opioid receptor

MOR:

μ-Opioid receptor

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Acknowledgements

This project was supported in part by the National Basic Research Program of China (973 program) and on the basis of an agreement between Max-Planck Society and Chinese Academy of Sciences. We also acknowledge the support from Green Valley Holding Co, Shanghai and from National Natural Science Foundation of China (Youth Program No. 81403489 to Y. Xu).

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Authors and Affiliations

  1. School of Medicine, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA

    Lu Pu Ph.D.

  2. Shanghai Research Center for Acupuncture and Meridians, Goushoujing Rd 199, Shanghai, 201203, People’s Republic of China

    Yinfang Xu Ph.D. & Wolfgang Schwarz Ph.D.

  3. Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai, 200433, People’s Republic of China

    Yinfang Xu Ph.D. & Wolfgang Schwarz Ph.D.

  4. Institute for Biophysics, Goethe-University Frankfurt, Max-von-Laue-Str. 1, 60438, Frankfurt am Main, Germany

    Wolfgang Schwarz Ph.D.

Authors
  1. Lu Pu Ph.D.
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  2. Yinfang Xu Ph.D.
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  3. Wolfgang Schwarz Ph.D.
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Corresponding author

Correspondence to Wolfgang Schwarz Ph.D. .

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Editors and Affiliations

  1. Univ of Texas Med Schl, Houston, Texas, USA

    Ying Xia

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Pu, L., Xu, Y., Schwarz, W. (2015). Regulation of Membrane Transporters by Delta-Opioid Receptors. In: Xia, Y. (eds) Neural Functions of the Delta-Opioid Receptor. Springer, Cham. https://doi.org/10.1007/978-3-319-25495-1_7

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