The neuronal and neuroendocrine peptides oxytocin (OT) and vasotocin (VT), including vasopressins... more The neuronal and neuroendocrine peptides oxytocin (OT) and vasotocin (VT), including vasopressins, have six cognate receptors encoded by six receptor subtype genes in jawed vertebrates. The peptides elicit a broad range of responses that are specifically mediated by the receptor subtypes including neuronal functions regulating behavior and hormonal actions on reproduction and water/electrolyte balance. Previously, we have demonstrated that these six receptor subtype genes, which we designated VTR1A, VTR1B, OTR, VTR2A, VTR2B and VTR2C, arose from a syntenic ancestral gene pair, one VTR1/OTR ancestor and one VTR2 ancestor, through the early vertebrate whole-genome duplications (WGD) called 1R and 2R. This was supported by both phylogenetic and chromosomal conserved synteny data. More recently, other studies have focused on confounding factors, such as the OTR/VTR orthologs in cyclostomes, to question this scenario for the origin of the OTR/VTR gene family; proposing instead less parsi...
The evolution of the opioid peptides and nociceptin/orphanin as well as their receptors has been ... more The evolution of the opioid peptides and nociceptin/orphanin as well as their receptors has been difficult to resolve due to variable evolutionary rates. By combining sequence comparisons with information on the chromosomal locations of the genes, we have deduced the following evolutionary scenario: The vertebrate predecessor had one opioid precursor gene and one receptor gene. The two genome doublings before the vertebrate radiation resulted in three peptide precursor genes whereupon a fourth copy arose by a local gene duplication. These four precursors diverged to become the prepropeptides for endorphin (POMC), enkephalins, dynorphins, and nociceptin, respectively. The ancestral receptor gene was quadrupled in the genome doublings leading to delta, kappa, and mu and the nociceptin/orphanin receptor. This scenario is corroborated by new data presented here for coelacanth and spotted gar, representing two basal branches in the vertebrate tree. A third genome doubling in the ancestor of teleost fishes generated additional gene copies. These results show that the opioid system was quite complex already in the first vertebrates and that it has more components in teleost fishes than in mammals. From an evolutionary point of view, nociceptin and its receptor can be considered full-fledged members of the opioid system.
The corticotropin releasing hormone receptors (CRHR) and the arthropod diuretic hormone 44 recept... more The corticotropin releasing hormone receptors (CRHR) and the arthropod diuretic hormone 44 receptors (DH44R) are structurally and functionally related members of the G protein-coupled receptors (GPCR) of the secretin-like receptor superfamily. We show here that they derive from a bilaterian predecessor. In protostomes, the receptor became DH44R that has been identified and functionally characterised in several arthropods but the gene seems to be absent from nematode genomes. Duplicate DH44R genes (DH44 R1 and DH44R2) have been described in some arthropods resulting from lineage-specific duplications. Recently, CRHR-DH44R-like receptors have been identified in the genomes of some lophotrochozoans (molluscs, which have a lineage-specific gene duplication, and annelids) as well as representatives of early diverging deuterostomes. Vertebrates have previously been reported to have two CRHR receptors that were named CRHR1 and CRHR2. To resolve their origin we have analysed recently assemb...
A peptide ending with RFamide (Arg-Phe-amide) was discovered independently by three different lab... more A peptide ending with RFamide (Arg-Phe-amide) was discovered independently by three different laboratories in 2003 and named 26RFa or QRFP. In mammals, a longer version of the peptide, 43 amino acids, was identified and found to bind to the orphan G protein-coupled receptor GPR103. We searched the genome database of Branchiostoma floridae (Bfl) for receptor sequences related to those that bind peptides ending with RFa or RYa (including receptors for NPFF, PRLH, GnIH, and NPY). One receptor clustered in phylogenetic analyses with mammalian QRFP receptors. The gene has 3 introns in Bfl and 5 in human, but all intron positions differ, implying that the introns were inserted independently. A QRFP-like peptide consisting of 25 amino acids and ending with RFa was identified in the amphioxus genome. Eight of the ten last amino acids are identical between Bfl and human. The prepro-QRFP gene in Bfl has one intron in the propeptide whereas the human gene lacks introns. The Bfl QRFP peptide was synthesized and the receptor was functionally expressed in human cells. The response was measured as inositol phosphate (IP) turnover. The Bfl QRFP peptide was found to potently stimulate the receptor's ability to induce IP turnover with an EC50 of 0.28nM. Also the human QRFP peptides with 26 and 43 amino acids were found to stimulate the receptor (1.9 and 5.1nM, respectively). Human QRFP with 26 amino acids without the carboxyterminal amide had dramatically lower potency at 1.3μM. Thus, we have identified an amphioxus QRFP-related peptide and a corresponding receptor and shown that they interact to give a functional response.
Molecular Evolution of the Major Histocompatibility Complex, 1991
The DRB genes of the human major histocompatibility complex display extensive polymorphism and va... more The DRB genes of the human major histocompatibility complex display extensive polymorphism and vary in number from one to four between haplotypes. Recently, the DRB genes have been classified into five allelic series. We review here the molecular organization of the various DR haplotypes and analyze the evolutionary relationships of the DRB genes. The variation in the number of DRB genes between haplotypes along with the complex similarities between allelic as well as nonallelic sequences makes definitive locus assignments difficult. We propose a simplistic view of the locus assignments of the DRB genes, which is based on 1) the relative chromosomal localization in the DR region, 2) which genes are linked on the same haplotype and, 3) the level of gene expression. These criteria can be met by a model system with only two expressed DRB loci, and two loci for the DRB pseudogenes. This model accepts the extensive variation between the presently recognized DRB alleles as being due to genetic exchange with nonallelic DRB genes.
Proceedings of the National Academy of Sciences, 1981
mRNA coding for mouse major transplantation antigens of the d haplotype was partially purified, c... more mRNA coding for mouse major transplantation antigens of the d haplotype was partially purified, copied into double-stranded cDNA, and cloned in Escherichia coli. Clones were selected by their ability to hybridize specifically with mRNA coding for H-2K, D, or L antigens. One of these clones, pH-2d-1, carries a 1200-base-pair insert, comprising the noncoding region, including poly(A) at the 3' end and part of the coding region. A partial sequence of the latter region showed extensive homology with the known amino acid sequences of H-2Kb,Kk, and HLA-B7 antigens. From this comparison, it appears that the coding region extends from amino acid 133 in the second domain, through the third domain, to the cytoplasmic COOH-terminal region. A stretch of 24 hydrophobic or uncharged residues, located 31 amino acids from the COOH-terminal end, could represent the segment that spans the membrane. This is followed on the cytoplasmic side of the membrane by a cluster of basic amino acids and a po...
The neuronal and neuroendocrine peptides oxytocin (OT) and vasotocin (VT), including vasopressins... more The neuronal and neuroendocrine peptides oxytocin (OT) and vasotocin (VT), including vasopressins, have six cognate receptors encoded by six receptor subtype genes in jawed vertebrates. The peptides elicit a broad range of responses that are specifically mediated by the receptor subtypes including neuronal functions regulating behavior and hormonal actions on reproduction and water/electrolyte balance. Previously, we have demonstrated that these six receptor subtype genes, which we designated VTR1A, VTR1B, OTR, VTR2A, VTR2B and VTR2C, arose from a syntenic ancestral gene pair, one VTR1/OTR ancestor and one VTR2 ancestor, through the early vertebrate whole-genome duplications (WGD) called 1R and 2R. This was supported by both phylogenetic and chromosomal conserved synteny data. More recently, other studies have focused on confounding factors, such as the OTR/VTR orthologs in cyclostomes, to question this scenario for the origin of the OTR/VTR gene family; proposing instead less parsi...
The evolution of the opioid peptides and nociceptin/orphanin as well as their receptors has been ... more The evolution of the opioid peptides and nociceptin/orphanin as well as their receptors has been difficult to resolve due to variable evolutionary rates. By combining sequence comparisons with information on the chromosomal locations of the genes, we have deduced the following evolutionary scenario: The vertebrate predecessor had one opioid precursor gene and one receptor gene. The two genome doublings before the vertebrate radiation resulted in three peptide precursor genes whereupon a fourth copy arose by a local gene duplication. These four precursors diverged to become the prepropeptides for endorphin (POMC), enkephalins, dynorphins, and nociceptin, respectively. The ancestral receptor gene was quadrupled in the genome doublings leading to delta, kappa, and mu and the nociceptin/orphanin receptor. This scenario is corroborated by new data presented here for coelacanth and spotted gar, representing two basal branches in the vertebrate tree. A third genome doubling in the ancestor of teleost fishes generated additional gene copies. These results show that the opioid system was quite complex already in the first vertebrates and that it has more components in teleost fishes than in mammals. From an evolutionary point of view, nociceptin and its receptor can be considered full-fledged members of the opioid system.
The corticotropin releasing hormone receptors (CRHR) and the arthropod diuretic hormone 44 recept... more The corticotropin releasing hormone receptors (CRHR) and the arthropod diuretic hormone 44 receptors (DH44R) are structurally and functionally related members of the G protein-coupled receptors (GPCR) of the secretin-like receptor superfamily. We show here that they derive from a bilaterian predecessor. In protostomes, the receptor became DH44R that has been identified and functionally characterised in several arthropods but the gene seems to be absent from nematode genomes. Duplicate DH44R genes (DH44 R1 and DH44R2) have been described in some arthropods resulting from lineage-specific duplications. Recently, CRHR-DH44R-like receptors have been identified in the genomes of some lophotrochozoans (molluscs, which have a lineage-specific gene duplication, and annelids) as well as representatives of early diverging deuterostomes. Vertebrates have previously been reported to have two CRHR receptors that were named CRHR1 and CRHR2. To resolve their origin we have analysed recently assemb...
A peptide ending with RFamide (Arg-Phe-amide) was discovered independently by three different lab... more A peptide ending with RFamide (Arg-Phe-amide) was discovered independently by three different laboratories in 2003 and named 26RFa or QRFP. In mammals, a longer version of the peptide, 43 amino acids, was identified and found to bind to the orphan G protein-coupled receptor GPR103. We searched the genome database of Branchiostoma floridae (Bfl) for receptor sequences related to those that bind peptides ending with RFa or RYa (including receptors for NPFF, PRLH, GnIH, and NPY). One receptor clustered in phylogenetic analyses with mammalian QRFP receptors. The gene has 3 introns in Bfl and 5 in human, but all intron positions differ, implying that the introns were inserted independently. A QRFP-like peptide consisting of 25 amino acids and ending with RFa was identified in the amphioxus genome. Eight of the ten last amino acids are identical between Bfl and human. The prepro-QRFP gene in Bfl has one intron in the propeptide whereas the human gene lacks introns. The Bfl QRFP peptide was synthesized and the receptor was functionally expressed in human cells. The response was measured as inositol phosphate (IP) turnover. The Bfl QRFP peptide was found to potently stimulate the receptor's ability to induce IP turnover with an EC50 of 0.28nM. Also the human QRFP peptides with 26 and 43 amino acids were found to stimulate the receptor (1.9 and 5.1nM, respectively). Human QRFP with 26 amino acids without the carboxyterminal amide had dramatically lower potency at 1.3μM. Thus, we have identified an amphioxus QRFP-related peptide and a corresponding receptor and shown that they interact to give a functional response.
Molecular Evolution of the Major Histocompatibility Complex, 1991
The DRB genes of the human major histocompatibility complex display extensive polymorphism and va... more The DRB genes of the human major histocompatibility complex display extensive polymorphism and vary in number from one to four between haplotypes. Recently, the DRB genes have been classified into five allelic series. We review here the molecular organization of the various DR haplotypes and analyze the evolutionary relationships of the DRB genes. The variation in the number of DRB genes between haplotypes along with the complex similarities between allelic as well as nonallelic sequences makes definitive locus assignments difficult. We propose a simplistic view of the locus assignments of the DRB genes, which is based on 1) the relative chromosomal localization in the DR region, 2) which genes are linked on the same haplotype and, 3) the level of gene expression. These criteria can be met by a model system with only two expressed DRB loci, and two loci for the DRB pseudogenes. This model accepts the extensive variation between the presently recognized DRB alleles as being due to genetic exchange with nonallelic DRB genes.
Proceedings of the National Academy of Sciences, 1981
mRNA coding for mouse major transplantation antigens of the d haplotype was partially purified, c... more mRNA coding for mouse major transplantation antigens of the d haplotype was partially purified, copied into double-stranded cDNA, and cloned in Escherichia coli. Clones were selected by their ability to hybridize specifically with mRNA coding for H-2K, D, or L antigens. One of these clones, pH-2d-1, carries a 1200-base-pair insert, comprising the noncoding region, including poly(A) at the 3' end and part of the coding region. A partial sequence of the latter region showed extensive homology with the known amino acid sequences of H-2Kb,Kk, and HLA-B7 antigens. From this comparison, it appears that the coding region extends from amino acid 133 in the second domain, through the third domain, to the cytoplasmic COOH-terminal region. A stretch of 24 hydrophobic or uncharged residues, located 31 amino acids from the COOH-terminal end, could represent the segment that spans the membrane. This is followed on the cytoplasmic side of the membrane by a cluster of basic amino acids and a po...
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Papers by Dan Larhammar