Coexpression of delta-opioid receptors with micro receptors in GH3 cells changes the functional response to micro agonists from inhibitory to excitatory

TY - JOUR

T1 - Coexpression of delta-opioid receptors with micro receptors in GH3 cells changes the functional response to micro agonists from inhibitory to excitatory

AU - Charles, Andrew C.

AU - Mostovskaya, Natalya

AU - Asas, Kathleen

AU - Evans, Christopher J.

AU - Dankovich, Megan L.

AU - Hales, Tim G.

PY - 2003/1

Y1 - 2003/1

N2 - GH3 cells show spontaneous activity characterized by bursts of action potentials and oscillations in [Ca 2+]i. This activity is modulated by the activation of exogenously expressed opioid receptors. In GH3 cells expressing only micro receptors (GH3MOR cells), the micro receptor-specific ligand [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) inhibited spontaneous Ca 2+ signaling by the inhibition of voltage-gated Ca 2+ channels, activation of inward-rectifying K+ channels, and inhibition of adenylyl cyclase. In contrast, in cells expressing both micro and delta receptors (GH3MORDOR cells), DAMGO had an excitatory effect on Ca 2+ signaling that was mediated by phospholipase C and release of Ca 2+ from intracellular stores. The excitatory effect of DAMGO was also inhibited by pretreatment with pertussis toxin. Despite the excitatory effect on Ca 2+ signaling, DAMGO inhibited Ca 2+ channels and activated inward-rectifying K+ channels in GH3MORDOR cells, although to a lesser extent than in GH3MOR cells. Long-term treatment with the delta receptor-specific ligand [D-Pen2,D-Pen5]-enkephalin reduced the excitatory effect of DAMGO in the majority of GH3MORDOR cells and restored the inhibitory response to DAMGO in some cells. The inhibitory effect of somatostatin on Ca 2+ signaling was not different in GH3MORDOR versus GH3MOR cells. These results indicate that interaction between micro- and delta-opioid receptors causes a change in the functional response to micro ligands, possibly by the formation of a micro/delta heterodimer with distinct functional properties.

AB - GH3 cells show spontaneous activity characterized by bursts of action potentials and oscillations in [Ca 2+]i. This activity is modulated by the activation of exogenously expressed opioid receptors. In GH3 cells expressing only micro receptors (GH3MOR cells), the micro receptor-specific ligand [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) inhibited spontaneous Ca 2+ signaling by the inhibition of voltage-gated Ca 2+ channels, activation of inward-rectifying K+ channels, and inhibition of adenylyl cyclase. In contrast, in cells expressing both micro and delta receptors (GH3MORDOR cells), DAMGO had an excitatory effect on Ca 2+ signaling that was mediated by phospholipase C and release of Ca 2+ from intracellular stores. The excitatory effect of DAMGO was also inhibited by pretreatment with pertussis toxin. Despite the excitatory effect on Ca 2+ signaling, DAMGO inhibited Ca 2+ channels and activated inward-rectifying K+ channels in GH3MORDOR cells, although to a lesser extent than in GH3MOR cells. Long-term treatment with the delta receptor-specific ligand [D-Pen2,D-Pen5]-enkephalin reduced the excitatory effect of DAMGO in the majority of GH3MORDOR cells and restored the inhibitory response to DAMGO in some cells. The inhibitory effect of somatostatin on Ca 2+ signaling was not different in GH3MORDOR versus GH3MOR cells. These results indicate that interaction between micro- and delta-opioid receptors causes a change in the functional response to micro ligands, possibly by the formation of a micro/delta heterodimer with distinct functional properties.

KW - Analgesics, Opioid/pharmacology

KW - Animals

KW - Barium/metabolism

KW - Calcium/metabolism

KW - Calcium Signaling/drug effects

KW - Cells, Cultured

KW - Electrophysiology

KW - Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology

KW - Enkephalin, D-Penicillamine (2,5)-/pharmacology

KW - Enzyme Inhibitors/pharmacology

KW - Estrenes/pharmacology

KW - Patch-Clamp Techniques

KW - Pertussis Toxin/pharmacology

KW - Pyrrolidinones/pharmacology

KW - Rats

KW - Receptors, Opioid, delta/metabolism

KW - Receptors, Opioid, mu/metabolism

KW - Somatostatin/pharmacology

KW - Thapsigargin/pharmacology

KW - Transfection

M3 - Article

C2 - 12488540

SN - 0026-895X

VL - 63

SP - 89

EP - 95

JO - Molecular Pharmacology

JF - Molecular Pharmacology

IS - 1

ER -