Table 2.
Summary of the key findings about μ-opioid receptor SNP signalling
| MOPr variant | Key observations | pEC50 WT | pEC50 SNP | Bmax WT | Bmax Var | Reference |
|---|---|---|---|---|---|---|
| N40D | Unchanged agonist affinity. Similar DAMGO stimulated GTPγS activation. | 7.0 – DAM | 6.7 – DAM | 5.5 pmol·mg−1 | 6.1 pmol·mg−1 | Befort et al., 2001 |
| Similar cAMP inhibition. Reduced D40 expression. | 9.1 – Mor 8.8 – M-6-G 7.9 – β-end | 9.0 – Mor 8.8 – M-6-G 7.8 – β-end | 4.8 pmol·mg−1 | 0.63 pmol mg−1 | Beyer et al., 2004 | |
| Three times increased β-endorphin affinity for D40 than WT, and three times increased potency for GIRK activation in D40 expressing Xenopus oocytes. | Not provided | Not provided | Not provided | Not provided | Bond et al., 1998 | |
| Different N/D40 stimulated PKA activity and ERK1/2 phosphylation after chronic morphine treatment. | N/A (1 μM morphine only) | N/A (1 μM morphine only) | 835 fmol·mg–1 | 830 fmol mg−1 | Deb et al. 2010 | |
| Similar inhibition of cAMP-stimulated CRE transcription. | 8.8 – DAM 8.8 – End-1 8.4 – L-Enk | 8.8 – DAM 8.9 – End-1 8.5 – L-Enk | Not provided | Similar to WT | Fortin et al., 2010 | |
| Decreased agonist potency to inhibit AC in D40-HEK293 and D40-AV-12 cells | 8.6 – DAM 8.4 – Mor 8.3 – Meth 8.4 – β-End | 8.1 – DAM* 7.8 – Mor* 7.8 – Meth* 8.1 – β-End | Not provided | 66% of WT | Kroslak et al., 2007 | |
| Decreased morphine potency for CaV inhibition in mouse trigeminal ganglion cells expressing ‘humanized’ D40. | 7.3 – Mor 7.2 – Fent | 6.6 – Mor* 7.0 – Fent* | Not provided | Similar to WT | Mahmoud et al., 2011 | |
| Increased DAMGO and morphine potency for CaV inhibition at D40 expressing rat SCG cells. | 7.5 – DAM 7.1 – Mor 7.1 – M-6-G 7.1 – End-1 | 7.8 – DAM* 7.4 – Mor* 7.1 – M-6-G 7.1 – End-1 | Not provided | Not provided | Margas et al., 2007 | |
| Decreased D40 expression in SII region of cortex in post-mortem brain. SII region-specific decrease in DAMGO efficacy in D40 carriers. | 5.9 – DAM | 6.0 – DAM | 97 fmol·mg–1 | 114 fmol mg−1 | Oertel et al., 2009 | |
| No difference in DAMGO potency at D40 for CaV inhibition in ‘humanized’ mouse trigeminal ganglion cells. | 7.2 – DAM 6.3 – β-End | 7.1 – DAM 6.2 – β-End | Not provided | Similar to WT | Ramchandani et al., 2011 | |
| Increased DAMGO potency for Cav2.2 inhibition in D40-HEK-293 cells. | 8.6 – DAM | 9.5 – DAM* | Not provided | Not provided | Lopez Soto & Raingo, 2012 | |
| Lower mRNA levels of G118 allele for heterozygous A118G carriers in post-mortem brain. Decreased G118 mRNA and 10-fold decreased D40 expression in CHO-K1 cells. | N/A | N/A | Not provided | Not provided | Zhang et al., 2005 | |
| A6V | Similar inhibition of cAMP-stimulated CRE transcription. | 8.8 – DAM 8.8 – End-1 8.4 – L-Enk | 8.6 – DAM 8.7 – End-1 8.2 – L-Enk | Not provided | Similar to WT | Fortin et al., 2010 |
| Unchanged agonist efficacy and potency for intracellular Ca release at A/V6 on MOR1A backbone. | 7.5 – DAM 7.4 – Mor | 7.9 – DAM 7.3 – Mor | 5.6 pmol·mg−1 | 5.8 pmol·mg−1 | Ravindranathan et al., 2009 | |
| S42C | Decreased agonist potency for intracellular Ca release at C42 on MOR1A backbone. | 7.5 – DAM 7.4 – Mor | >6.8 – DAM* >6.8 – Mor* | 2.7 pmol·mg−1 | 5.8 pmol·mg−1 | Ravindranathan et al., 2009 |
| D51N | Similar inhibition of cAMP-stimulated CRE transcription. | 8.8 – DAM 8.8 – End-1 8.4 – L-Enk | 8.6 – DAM 8.8 – End-1 8.4 – L-Enk | Not provided | Similar to WT | Fortin et al., 2010 |
| G63V | Similar inhibition of cAMP-stimulated CRE transcription. | 8.8 – DAM 8.8 – End-1 8.4 – L-Enk | 9.0 – DAM 8.9 – End-1 8.5 – L-Enk | Not provided | Similar to WT | Fortin et al., 2010 |
| S66F | Decreased potency of DAMGO and endormorphin 1 at F66 for inhibition of cAMP-stimulated CRE transcription. | 8.8 – DAM 8.8 – End-1 8.4 – L-Enk | 8.2 – DAM* 8.3 – End-1* 7.7 – L-Enk* | Not provided | Similar to WT | Fortin et al., 2010 |
| L85I (L83I) | Increased morphine stimulated endocytosis in I83-HEK293 cells. Decreased agonist efficacy in inhibition of AC and ERK phosphorylation. | 6.7 – DAM 6.7 – Mor | 6.5 – DAM 6.9 – Mor | 1.8 pmol mg−1 | 2.7 pmol mg−1 | Cooke et al., 2014 |
| L85I | Increased morphine stimulated endocytosis in I85-HEK293 cells. Increased AC super activation in I85 HEK-293 cells. No change in agonist potency. | 7.5 – DAM 7.4 – Mor | 7.9 – DAM 7.7 – Mor | 5.6 pmol mg−1 | 5.2 pmol mg−1 | Ravindranathan et al., 2009 |
| S147C | Decreased agonist potency for inhibition of cAMP-stimulated CRE transcription. | 8.8 – DAM 8.8 – End-1 8.4 – L-Enk | 8.3 – DAM* 8.4 – End-1* 7.9 – L-Enk* | Not provided | Similar to WT | Fortin et al., 2010 |
| Increased agonist potency for intracellular Ca release at C147 on MOR1A backbone. | 7.5 – DAM 7.4 – Mor | 7.9 – DAM* 8.3 – Mor* | 5.6 pmol·mg−1 | 5.0 pmol·mg−1 | Ravindranathan et al., 2009 | |
| N152D | Decrease in morphine affinity for D152 in COS cells. | N/A | N/A | 5.5 pmol·mg−1 | 1.9 pmol·mg−1 | Befort et al., 2001 |
| R181C | HEK-293 cells expressing C181 failed to signal via DAMGO or morphine. | 7.5 – DAM 7.4 – Mor | N/A | 5.6 pmol·mg−1 | 3.5 pmol·mg−1 | Ravindranathan et al., 2009 |
| N190K | Decreased K190 expression in HEK-293 cells. Treatment with naloxone and naltrexone both increased K190 expression and inhibition of cAMP-stimulated CRE transcription. | Not provided | Not provided | Not provided | N/A | Fortin et al., 2010 |
| N192F | Decreased agonist potency at F192 for intracellular calcium release in HEK-293 cells expressing F192 on MOR1A backbone. | 7.5 – DAM 7.4 – Mor | >6.8 – DAM* >6.8 – Mor* | 5.6 pmol·mg−1 | 4.4 pmol·mg−1 | Ravindranathan et al., 2009 |
| R260H | Decreased basal GTPγS activity at H260 in HEK293 cells. Slight decrease in morphine stimulated GTPγS at H260, and slight decrease in affinity of H260 for CaM. | 8.4 – Mor | 8.6 – Mor | 3.5 pmol·mg−1 | 3.9 pmol·mg−1 | Wang et al., 2001 |
| R265H | Decreased basal GTPγS activity at H260 in COS cells. Slight decrease in maximal DAMGO stimulated GTPγS at H260. | 7.0 – DAM | 6.9 – DAM | 5.5 pmol·mg−1 | 4.6 pmol·mg−1 | Befort et al., 2001 |
| Decreased agonist potency for inhibition of cAMP-stimulated CRE transcription. | 8.8 – DAM 8.8 – End-1 8.4 – L-Enk | 8.0 – DAM* 8.1 – End-1* 7.6 – L-Enk* | Not provided | Similar to WT | Fortin et al., 2010 | |
| Decreased basal GTPγS activity at H265 in HEK293 cells. Slight decrease in maximal morphine stimulated GTPγS at H265. Decreased affinity of H265 for CaM binding, and decreased desensitization following morphine pretreatment. | 8.4 – Mor | 8.5 – Mor | 3.5 pmol·mg−1 | 4.2 pmol·mg−1 | Wang et al., 2001 | |
| S268P | No of agonist-stimulated GTPγS binding in COS cells. Decreased agonist potency and efficacy at P268 for inhibition of cAMP accumulation. | 7.2 – DAM 6.5 – β-End 6.2 – Mor | 6.4 – DAM* 5.9 – β-End* 5.8 – Mor* | 5.5 pmol·mg−1 | 3.6 pmol·mg−1 | Befort et al., 2001 |
| Decreased potency of DAMGO and endomorphin-1 for inhibition of cAMP-stimulated CRE transcription. | 8.8 – DAM 8.8 – End-1 8.4 – L-Enk | 8.2 – DAM* 8.4 – End-1* 7.9 – L-Enk | Not provided | Similar to WT | Fortin et al., 2010 | |
| Decreased GTPγS binding, slower desensitization and decreased AC inhibition in response to DAMGO. | N/A | N/A | 643 fmol·mg–1 | 340 fmol·mg–1 | Koch et al., 2000 | |
| Decreased morphine potency at P268 for inhibition of cAMP accumulation. | 7.0 – Mor | 6.3 – Mor* | 3.5 pmol·mg−1 | 4.5 pmol·mg−1 | Wang et al., 2001 | |
| D274N | Increased agonist potency for inhibition of cAMP-stimulated CRE transcription. | 8.8 – DAM 8.8 – End-1 8.4 – L-Enk | 9.1 – DAM* 8.3 – End-1* 8.6 – L-Enk* | Not provided | Similar to WT | Fortin et al., 2010 |
| V293I | Unchanged in agonist potency for inhibition of cAMP accumulation. | 8.8 – DAM 8.8 – End-1 8.4 – L-Enk | 8.8 – DAM 8.8 – End-1 8.4 – L-Enk | Not provided | Similar to WT | Fortin et al., 2010 |
*
P < 0.05, from original publications. Abbreviations: β-End, β-endorphin; DAM, DAMGO; End-1, endomorphin 1; Fent, fentanyl; L-ENK, [Leu]5enkephalin; Meth, methadone; Mor, morphine; MOR1A, μ-opioid receptor 1A splice variant; SCG, superior cervical ganglion.