ADGRL1 | Adhesion Class GPCRs | IUPHAR/BPS Guide to PHARMACOLOGY

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ADGRL1

Target not currently curated in GtoImmuPdb

Target id: 206

Nomenclature: ADGRL1

Family: Adhesion Class GPCRs

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

Gene and Protein Information
Adhesion G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 1474 19p13.2 ADGRL1 adhesion G protein-coupled receptor L1
Mouse 7 1466 8 3 Adgrl1 adhesion G protein-coupled receptor L1
Rat 7 1515 19q11 Adgrl1 adhesion G protein-coupled receptor L1
Previous and Unofficial Names
LPHN1 (latrophilin 1) | LEC1 (lectomedin-2) | CIRL1 (calcium-independent alpha-latrotoxin 1) | CL1 (CIRL/latrophilin 1)
Database Links
Specialist databases
GPCRDB lphn1_human (Hs), lphn1_mouse (Mm), agrl1_rat (Rn)
Other databases
CATH/Gene3D
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Mouse Latrophilin-1 GPCR Gal_lectin domain in complex with Rhamnose-solution structure
PDB Id:  2JXA
Resolution:  0.0Å
Species:  Mouse
References:  24
Image of receptor 3D structure from RCSB PDB
Description:  Solution structure of the Gal_lectin domain of mouse Latrophilin-1 GPCR
PDB Id:  2JX9
Resolution:  0.0Å
Species:  Mouse
References:  24
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the GAIN and HormR domains of CIRL 1/Latrophilin 1 (CL1)
PDB Id:  4DLQ
Resolution:  1.85Å
Species:  Rat
References:  1
Natural/Endogenous Ligands
lasso D

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Agonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
α-latrotoxin Rn Full agonist 9.6 – 9.8 pKd 12,25
pKd 9.6 – 9.8 (Kd 2.6x10-10 – 1.6x10-10 M) [12,25]
LTX(N4C) Rn Full agonist 9.6 pKd 25
pKd 9.6 (Kd 2.6x10-10 M) [25]
lasso D Rn Partial agonist 8.8 pKd 21
pKd 8.8 (Kd 1.7x10-9 M) [21]
Agonist Comments
Neurexins 1β, 2β and 1α have been reported to bind ADGRL1 but have not been shown to stimulate it or cause any effect, except limited increase in adhesion between ADGRL1-transfected and NRXN-transfected HEK293 cells [5].

O'Sullivan et al. suggest in their 2012 publication that ADGRL1 might interact with FLRT3; however, the paper mainly deals with ADGRL3 and shows only indirect data on ADGRL1/FLRT3 interaction and does not report any physiological effect of any such interaction [17].
Primary Transduction Mechanisms
Transducer Effector/Response
Gq/G11 family Phospholipase C stimulation
Potassium channel
Calcium channel
References:  10,13-14,18,20-21,26
Secondary Transduction Mechanisms
Transducer Effector/Response
G protein (identity unknown) Adenylate cyclase stimulation
Comments:  The involvement of G proteins has not been shown in this case, although ADGRL1 has been demonstrated to bind G0 and Gq, but not Gi [14,18].
References:  14
Tissue Distribution
Brain. Detectable in kidney, pancreas, heart, lung, placenta. Not detectable in liver
Species:  Human
Technique:  Northern blot
References:  22
Brain. Detectable in heart, lung, kidney, pancreas and other tissues. Not detectable in liver
Species:  Mouse
Technique:  RT-PCR
References:  8,19
Brain - all regions. Detectable in kidney, spleen, lung and other tissues. Not detectable in liver
Species:  Rat
Technique:  Northern Blot, RT-PCR and Western blot
References:  8-9,14,16,21
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
Neurotransmitter release
Species:  Rat
Tissue:  Brain synaptosomes
Response measured:  Release of [14C]-glutamate and [3H]γ-aminobutyric acid
References:  2
Intracellular calcium concentration
Species:  Mouse
Tissue:  Neuroblastoma cell line, NB2a
Response measured:  Increase in cytosolic calcium concentration; release of calcium from intracellular stores
References:  26
Neurotransmitter release
Species:  Rat
Tissue:  Hippocampal neuronal culture
Response measured:  Increased frequency of mEPSCs
References:  7
Neurotransmitter release
Species:  Mouse
Tissue:  Neuromuscular junction, flexor digitorum brevis
Response measured:  Increased frequency of mepps
References:  15
Physiological Consequences of Altering Gene Expression
Mice with ADGRL1 knockout demonstrate abnormal maternal nurturing
Species:  Mouse
Tissue:  Full body
Technique:  Gene knockouts
References:  23
Xenobiotics Influencing Gene Expression
Increase in ADGRL1 expression
Species:  Rat
Tissue:  Frontal cortex
Technique:  Administration of risperidone, 4 weeks, 1 mg/kg. qPCR; cDNA microarray
References:  6
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Lphn1tm1Sud Lphn1tm1Sud/Lphn1tm1Sud
involves: 129S6/SvEvTac * C57BL/6
MGI:1929461  MP:0001386 abnormal maternal nurturing PMID: 11741895 
Lphn1tm1Sud Lphn1tm1Sud/Lphn1tm1Sud
involves: 129S6/SvEvTac * C57BL/6
MGI:1929461  MP:0003633 abnormal nervous system physiology PMID: 11741895 
Lphn1tm1Sud|Nrxn1tm1Sud Lphn1tm1Sud/Lphn1tm1Sud,Nrxn1tm1Sud/Nrxn1tm1Sud
involves: 129S6/SvEvTac * C57BL/6
MGI:1096391  MGI:1929461  MP:0003633 abnormal nervous system physiology PMID: 11741895 
Lphn1tm1Sud|Nrxn1tm1Sud Lphn1tm1Sud/Lphn1tm1Sud,Nrxn1tm1Sud/Nrxn1tm1Sud
involves: 129S6/SvEvTac * C57BL/6
MGI:1096391  MGI:1929461  MP:0004494 abnormal synaptic glutamate release PMID: 11741895 
Lphn1tm1Sud Lphn1tm1Sud/Lphn1tm1Sud
involves: 129S6/SvEvTac * C57BL/6
MGI:1929461  MP:0004495 decreased synaptic glutamate release PMID: 11741895 
Lphn1tm1Sud|Nrxn1tm1Sud Lphn1tm1Sud/Lphn1tm1Sud,Nrxn1tm1Sud/Nrxn1tm1Sud
involves: 129S6/SvEvTac * C57BL/6
MGI:1096391  MGI:1929461  MP:0004495 decreased synaptic glutamate release PMID: 11741895 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Mental retardation, hearing impairment, cranial malformations, hyperactivity
References:  4
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Microdeletion Human - - 19p13.12. Deletion of 2.1 Mb with breakpoints at 13.965–13.933 Mb and 16.053–16.118 Mb 4
Disease:  Mental retardation, language delay, hyperactivity, aggression, hearing impairment, cranial malformation, seizures
References:  4
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Microdeletion Human - - 19p13.12. Deletion of 1.9 Mb with breakpoints at 14.119–14.135 Mb and 16.053–16.071 Mb 4
Disease:  Speech and neuromotor retardation, hyperactivity, cranial malformation, seizures
References:  4
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Microdeletion Human - - 19p13.12-p13.3. Deletion of 1.5 Mb with breakpoints at 12.870–12.878 Mb and 14.154–14.166 Mb 4
General Comments
ADGRL1 (adhesion G protein-coupled receptor L1, formerly LPHN1 or latrophilin 1) is a receptor that belongs to Family I Adhesion-GPCRs along with ADGRL2 (latrophilin 2), ADGRL3 (latrophilin 3) and ADGRL4 (ELTD1) [3]. Family I Adhesion-GPCRs have orthologs in vertebrate and invertebrate species. There are clear problems with the distribution of ADGRL1 as determined by different techniques. Multiple Northern and Western blotting experiments [9,14,16,21-22] demonstrate that ADGRL1 mRNA and protein are distributed very similarly in rat and human tissues: ADGRL1 is almost exclusively expressed in the brain, is barely detectable in kidneys, lung and pancreas, and is undetectable in the liver. However, the two qPCR datasets [8,19] contradict both these data and each other. According to [8] ADGRL1 is ubiquitous in the rat and is highly abundant in rat liver, which is inconsistent with the blotting data. On the other hand, the same dataset reports that ADGRL1 is brain-specific in the mouse and is undetectable in mouse liver. While consistent with blotting, this clearly contradicts the second qPCR dataset [19], which shows that ADGRL1 is ubiquitous in the mouse and is highly expressed in mouse liver. One possible reason for this conflict could be a varying degree of contamination of tissue samples with autonomic neurons and endocrine cells, which both highly express ADGRL1. Like most other Adhesion-GPCRs, ADGRL1 is cleaved post-translationally into two subunits: α (also called N-terminal fragment, NTF) and β (also called C-terminal fragment, CTF) [11,26]. These subunits can behave as separate proteins on the cell surface; their re-association is driven by exogenous agonist binding and leads to intracellular calcium signalling [20,26]. This feature is not completely understood but is crucial for the functions of ADGRL1 and many other Adhesion GPCRs. There are multiple splice variants of ADGRL1 in all organisms, and the rat variant currently listed on the IUPHAR website (1515 amino acids) is less similar to the human ADGRL1 and less common than the two most abundant splice variants of rat ADGRL1 (1469 aa, accession AAC98700, [14]; and 1471 aa, accession NP_075251, [12]). One phenotype was in fact reported in the original paper on LPHN1-KO [23]: 'abnormal maternal nurturing' (Phenotype ID MP 0001386). Other phenotypes, like 'abnormal and decreased synaptic glutamate release' (MP 0004494 and MP 0004495) were seen only in response to toxin (α-latrotoxin) application and were not observed under physiological conditions.

The Gal_lectin domain is now termed rhamnose-binding lectin (RBL) domain.

References

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1. Araç D, Boucard AA, Bolliger MF, Nguyen J, Soltis SM, Südhof TC, Brunger AT. (2012) A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis. EMBO J., 31 (6): 1364-78. [PMID:22333914]

2. Ashton AC, Volynski KE, Lelianova VG, Orlova EV, Van Renterghem C, Canepari M, Seagar M, Ushkaryov YA. (2001) alpha-Latrotoxin, acting via two Ca2+-dependent pathways, triggers exocytosis of two pools of synaptic vesicles. J. Biol. Chem., 276 (48): 44695-703. [PMID:11572875]

3. Bjarnadóttir TK, Fredriksson R, Höglund PJ, Gloriam DE, Lagerström MC, Schiöth HB. (2004) The human and mouse repertoire of the adhesion family of G-protein-coupled receptors. Genomics, 84 (1): 23-33. [PMID:15203201]

4. Bonaglia MC, Marelli S, Novara F, Commodaro S, Borgatti R, Minardo G, Memo L, Mangold E, Beri S, Zucca C et al.. (2010) Genotype-phenotype relationship in three cases with overlapping 19p13.12 microdeletions. Eur. J. Hum. Genet., 18 (12): 1302-9. [PMID:20648052]

5. Boucard AA, Ko J, Südhof TC. (2012) High affinity neurexin binding to cell adhesion G-protein-coupled receptor CIRL1/latrophilin-1 produces an intercellular adhesion complex. J. Biol. Chem., 287 (12): 9399-413. [PMID:22262843]

6. Chen ML, Chen CH. (2005) Microarray analysis of differentially expressed genes in rat frontal cortex under chronic risperidone treatment. Neuropsychopharmacology, 30 (2): 268-77. [PMID:15536490]

7. Deák F, Liu X, Khvotchev M, Li G, Kavalali ET, Sugita S, Südhof TC. (2009) Alpha-latrotoxin stimulates a novel pathway of Ca2+-dependent synaptic exocytosis independent of the classical synaptic fusion machinery. J. Neurosci., 29 (27): 8639-48. [PMID:19587270]

8. Haitina T, Olsson F, Stephansson O, Alsiö J, Roman E, Ebendal T, Schiöth HB, Fredriksson R. (2008) Expression profile of the entire family of Adhesion G protein-coupled receptors in mouse and rat. BMC Neurosci, 9: 43. [PMID:18445277]

9. Ichtchenko K, Bittner MA, Krasnoperov V, Little AR, Chepurny O, Holz RW, Petrenko AG. (1999) A novel ubiquitously expressed alpha-latrotoxin receptor is a member of the CIRL family of G-protein-coupled receptors. J. Biol. Chem., 274 (9): 5491-8. [PMID:10026162]

10. Ichtchenko K, Khvotchev M, Kiyatkin N, Simpson L, Sugita S, Südhof TC. (1998) alpha-latrotoxin action probed with recombinant toxin: receptors recruit alpha-latrotoxin but do not transduce an exocytotic signal. EMBO J., 17 (21): 6188-99. [PMID:9799228]

11. Krasnoperov V, Lu Y, Buryanovsky L, Neubert TA, Ichtchenko K, Petrenko AG. (2002) Post-translational proteolytic processing of the calcium-independent receptor of alpha-latrotoxin (CIRL), a natural chimera of the cell adhesion protein and the G protein-coupled receptor. Role of the G protein-coupled receptor proteolysis site (GPS) motif. J. Biol. Chem., 277 (48): 46518-26. [PMID:12270923]

12. Krasnoperov VG, Bittner MA, Beavis R, Kuang Y, Salnikow KV, Chepurny OG, Little AR, Plotnikov AN, Wu D, Holz RW et al.. (1997) alpha-Latrotoxin stimulates exocytosis by the interaction with a neuronal G-protein-coupled receptor. Neuron, 18 (6): 925-37. [PMID:9208860]

13. Lajus S, Vacher P, Huber D, Dubois M, Benassy MN, Ushkaryov Y, Lang J. (2006) Alpha-latrotoxin induces exocytosis by inhibition of voltage-dependent K+ channels and by stimulation of L-type Ca2+ channels via latrophilin in beta-cells. J. Biol. Chem., 281 (9): 5522-31. [PMID:16301314]

14. Lelianova VG, Davletov BA, Sterling A, Rahman MA, Grishin EV, Totty NF, Ushkaryov YA. (1997) Alpha-latrotoxin receptor, latrophilin, is a novel member of the secretin family of G protein-coupled receptors. J. Biol. Chem., 272 (34): 21504-8. [PMID:9261169]

15. Lelyanova VG, Thomson D, Ribchester RR, Tonevitsky EA, Ushkaryov YA. (2009) Activation of alpha-latrotoxin receptors in neuromuscular synapses leads to a prolonged splash acetylcholine release. Bull. Exp. Biol. Med., 147 (6): 701-3. [PMID:19902061]

16. Matsushita H, Lelianova VG, Ushkaryov YA. (1999) The latrophilin family: multiply spliced G protein-coupled receptors with differential tissue distribution. FEBS Lett., 443 (3): 348-52. [PMID:10025961]

17. O'Sullivan ML, de Wit J, Savas JN, Comoletti D, Otto-Hitt S, Yates 3rd JR, Ghosh A. (2012) FLRT proteins are endogenous latrophilin ligands and regulate excitatory synapse development. Neuron, 73 (5): 903-10. [PMID:22405201]

18. Rahman MA, Ashton AC, Meunier FA, Davletov BA, Dolly JO, Ushkaryov YA. (1999) Norepinephrine exocytosis stimulated by alpha-latrotoxin requires both external and stored Ca2+ and is mediated by latrophilin, G proteins and phospholipase C. Philos. Trans. R. Soc. Lond., B, Biol. Sci., 354 (1381): 379-86. [PMID:10212487]

19. Regard JB, Sato IT, Coughlin SR. (2008) Anatomical profiling of G protein-coupled receptor expression. Cell, 135 (3): 561-71. [PMID:18984166]

20. Silva JP, Lelianova V, Hopkins C, Volynski KE, Ushkaryov Y. (2009) Functional cross-interaction of the fragments produced by the cleavage of distinct adhesion G-protein-coupled receptors. J. Biol. Chem., 284 (10): 6495-506. [PMID:19124473]

21. Silva JP, Lelianova VG, Ermolyuk YS, Vysokov N, Hitchen PG, Berninghausen O, Rahman MA, Zangrandi A, Fidalgo S, Tonevitsky AG et al.. (2011) Latrophilin 1 and its endogenous ligand Lasso/teneurin-2 form a high-affinity transsynaptic receptor pair with signaling capabilities. Proc. Natl. Acad. Sci. U.S.A., 108 (29): 12113-8. [PMID:21724987]

22. Sugita S, Ichtchenko K, Khvotchev M, Südhof TC. (1998) alpha-Latrotoxin receptor CIRL/latrophilin 1 (CL1) defines an unusual family of ubiquitous G-protein-linked receptors. G-protein coupling not required for triggering exocytosis. J. Biol. Chem., 273 (49): 32715-24. [PMID:9830014]

23. Tobaben S, Südhof TC, Stahl B. (2002) Genetic analysis of alpha-latrotoxin receptors reveals functional interdependence of CIRL/latrophilin 1 and neurexin 1 alpha. J. Biol. Chem., 277 (8): 6359-65. [PMID:11741895]

24. Vakonakis I, Langenhan T, Prömel S, Russ A, Campbell ID. (2008) Solution structure and sugar-binding mechanism of mouse latrophilin-1 RBL: a 7TM receptor-attached lectin-like domain. Structure, 16 (6): 944-53. [PMID:18547526]

25. Volynski KE, Capogna M, Ashton AC, Thomson D, Orlova EV, Manser CF, Ribchester RR, Ushkaryov YA. (2003) Mutant alpha-latrotoxin (LTXN4C) does not form pores and causes secretion by receptor stimulation: this action does not require neurexins. J. Biol. Chem., 278 (33): 31058-66. [PMID:12782639]

26. Volynski KE, Silva JP, Lelianova VG, Atiqur Rahman M, Hopkins C, Ushkaryov YA. (2004) Latrophilin fragments behave as independent proteins that associate and signal on binding of LTX(N4C). EMBO J., 23 (22): 4423-33. [PMID:15483624]

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