General

Glucagon, glucagon-like peptide 1 (GLP-1), and glucagon-like peptide 2 (GLP-2) are peptide hormones encoded by a single common prohormone precursor, proglucagon [6,62]. The sequence of 29 amino acid (aa) pancreatic glucagon is highly conserved in mammals. Glucagon is synthesised mainly in islet A cells and the brain and has also been localised to specific cells in the stomach and intestine in some species [61]. Further processing of glucagon may also produce the C-terminal undecapeptide miniglucagon, a powerful inhibitor of insulin secretion [23].

Glucagon

Glucagon regulates blood glucose via control of hepatic glycogenolysis and gluconeogenesis [94] and via regulation of insulin release from the β cell [68,110]. Pharmacological administration of glucagon increases blood glucose in normal and diabetic subjects [98], and produces positive inotropic and chronotropic cardiovascular effects [144], relaxation of smooth muscle in the gastrointestinal tract and stimulation of growth hormone secretion [90].

The actions of glucagon are mediated via a single adenylate cyclase-coupled glucagon receptor [103] that also couples to the phospholipase C-inositol phosphate (PLC--IP) pathway leading to Ca²⁺ release from intracellular stores [141]. Cloning of the glucagon receptor cDNAs [67,124] identified a seven-transmembrane domain (7TM) receptor localised to human chromosome 17q25 [77]. The rat and mouse glucagon receptors are 485aa, 7TM proteins with four N-linked glycosylation sites and a RLAR sequence in the third intracellular loop, a motif known to be required for G protein activation [13,67,77,124]. The human receptor cDNA encodes a 477aa receptor that contains a similar (RLAK) G protein-coupling motif as well as four N-linked glycosylation sites [13,77,80].

Glucagon-like peptide-1

Peptidergic signals derived from the intestine augment the insulin response induced by nutrients (the 'incretin effect') [31]. This functional connection between intestine and the islets of Langerhans was termed the 'incretin axis' or 'entero-insular-axis' [31]. The gut-derived GLP-1 is an important mediator in this axis [25].

Glucagon-like peptide 1 is a major end-product of the post-translational processing of proglucagon in the intestinal L-cells. At the pancreatic β-cells it stimulates insulin release via specific receptors in a glucose-dependent manner. In addition to its potent insulinotropic action, GLP-I suppresses glucagon secretion from the islet α-cells, and increases proinsulin gene transcription and insulin production [25]. Glucagon-like peptide 1 has CNS effects resulting in delayed gastric emptying [114] and appetite regulation [52,133].

Glucagon-like peptide 1 receptors were initially identified on rat insulinoma-derived cells [28,38] and, subsequently, in other insulinoma cells [31] as well as on rat [92] and human pancreatic islet cells, somatostatin-secreting cells [32,49], isolated rat parietal cells [115,134], human gastric cancer cells (HGT-1) [58], solubilised membranes of rat epididymal adipose tissue [136], 3T3-L1 adipocytes [93], membranes from the rodent thyrotrope cell line α-TSH [4], and in rat lung [105-106] and brain [55,117,135,142].

Analysis of data obtained from binding experiments with RINm5F cells revealed that GLP-1 binds to a single class of binding sites [38]. Cross-linking studies with ¹²⁵[I]-GLP-1 demonstrate a single band with an apparent molecular mass of 63,000 [54,56]. The GLP-1 receptor protein is glycosylated and this is important for its function [39].

Molecular characterization of the GLP-1 receptor was achieved by cloning the rat and human β-cell GLP-1 receptor cDNAs [48,127-128,137,143] followed by isolation of cDNAs encoding the rat lung and the brain GLP-1 receptor [39,48,54,56,72,127-128,137,142-143]. The receptor protein consists of 463aa. At the amino acid level, rat and human GLP-1 receptors exhibit 90% sequence identity. The amino acid sequence contains a large hydrophilic, extracellular domain preceded by a short leader sequence required for receptor translocation across the endoplasmic reticulum during biosynthesis, and seven hydrophobic, membrane spanning domains that are linked by hydrophilic intra- and extracellular loops [129].

The human GLP-1 receptor gene has been localised to the long arm of chromosome 6 [122]. The GLP-1 receptor gene spans 40kb and consists of at least seven exons. The 5' flanking (promoter) region of the human GLP-1 receptor gene has been cloned and functionally characterized [71]. The cell- and tissue-specific expression of the GLP-1 receptor is mainly achieved by silencing cis-regulatory elements located between -574 and -2921 [40,146].

Studies investigating the distribution of rat and human GLP-1 receptor mRNA by sensitive methods such as RNAse protection assay and RT-PCR, detected GLP-1 receptor mRNA transcripts in pancreatic islets, lung, brain, stomach, heart and kidney but not in liver, skeletal muscle or adipose tissue of most species [11,39-40,48,54,56,71-72,122,127-129,137,142-143,146].

The GLP-1 receptor is functionally coupled to adenylate cyclase via a stimulatory G protein. Glucagon-like peptide 1-binding at pancreatic β-cells increases free cytosolic Ca²⁺ concentrations after cell depolarization [53,64-65,78,147]. Glucagon-like peptide 1 may enhance cytosolic Ca²⁺ independently of protein kinase A [8].

Homologous desensitization and internalization of the GLP-1 receptor are strictly dependent on the phosphorylation of three serine doublets within the cytoplasmatic tail [145]. Experiments with mutant GLP-1 receptors reveal that the number of phosphorylation sites correlates with the extent of desensitization and internalization. However, the two processes showed a different quantitative impairment in single and double mutants suggesting control by different molecular mechanisms [145].

For a recent review on review the current understanding of the structures of GLP-1 and GLP-1R, the molecular basis of their interaction, and the signaling events associated with it, see de Graaf et al., 2016 [47].

Glucagon-like peptide 2

Glucagon-like peptide 2 was first identified as a novel peptide encoded within the mammalian proglucagon cDNA sequence 3' of the sequence encoding to GLP-1 [5-6]. The GLP-2 amino acid sequence is flanked by pairs of dibasic residues characteristic of prohormone cleavage sites. Glucagon-like peptide 2 is co-secreted along with GLP-1 and glicentin from intestinal endocrine cells. The principal role of GLP-2 appears to be the maintenance of growth and absorptive function of the intestinal mucosal villus epithelium [26]. Glucagon-like peptide 2 administration to rodents enhances villus growth and increases small bowel mass, with weaker but detectable trophic effects observed in the large bowel and stomach [27,130-131]. Glucagon-like peptide 2 also upregulates hexose transport and nutrient absorption [10,19] and enhances sugar absorption and intestinal adaptation in rats with major small bowel resection [116]. Although GLP-2 binding sites have not yet been reported on cell lines and tissues, a GLP-2 receptor was isolated from hypothalamic and intestinal cDNA libraries using a combined PCR-expression cloning approach [96]. Consistent with the finding that GLP-2 stimulates adenylate cyclase activity in hypothalamic and pituitary membranes [96], GLP-2 increases intracellular cAMP in fibroblasts transfected with the rat or human GLP-2 receptor cDNA [96,149]. The GLP-2 receptor appears highly specific for GLP-2, and is expressed predominantly in the gastrointestinal tract and CNS.

Gastric inhibitory polypeptide

Gastric inhibitory polypeptide (GIP), also known as glucose-dependent inhibitory polypeptide is synthesised in and secreted from enteroendocrine K-cells in the duodenum and jejunum. Although originally identified as an inhibitor of gastric acid secretion, the best known action of GIP is the potentiation of glucose-dependent insulin secretion via GIP receptors expressed on islet β-cells. Evidence from studies using GIP receptor antagonists and GIP receptor -/- mice demonstrates the physiological importance of GIP action for the normal cell secretory response to glucose [91,132]. The actions of GIP are modulated by the physiological degradation of the peptide via N-terminal cleavage by the aminopeptidase dipeptidyl peptidase IV [69].

Secretin

The term 'hormone' was introduced by Bayliss and Starling almost one hundred years ago in response to the observation that a compound extracted from the duodenum could stimulate pancreatic fluid secretion [3]. This secretin molecule was subsequently purified and identified as a linear 27-residue peptide [97]. While species differences in this hormone have subsequently been found, with minimal differences in bovine, canine, rat, and human forms and substantial differences in chicken secretin, molecular variants or alternate forms have not yet been reported in any single species [16-17,46,100,118]. Secretin is produced and secreted by scattered single endocrine cells within the proximal intestinal mucosa (S-cells) in response to luminal acid and fatty acids [112]. Well-established, physiologically relevant targets for this hormone include the ductular epithelial cells in the pancreas and biliary tree, where secretin stimulates alkaline secretion to neutralise the luminal acid and thereby protect the intestinal mucosa [148]. In addition, stimulation of both pepsinogen and Brunner's gland secretion, and slowing of gastric emptying and intestinal transit all contribute to an optimal intraluminal milieu for digestion [12]. All these actions are currently explained by the activity of a single molecular form of secretin on a single form of the secretin receptor. Central nervous system and cardiac effects of this hormone have also been described. Unfortunately, an adequately selective small molecule, orally active secretin receptor agonist or antagonist has not yet been described.

Growth hormone-releasing hormone

Growth hormone-releasing hormone (GHRH) was initially isolated from pancreatic tumours that caused acromegaly [51,107], and later characterized from the hypothalamus [76,119] based on its ability to stimulate growth hormone secretion from primary cultures of rat pituitary cells. Growth hormone-releasing hormone is released from neurosecretory cells in the arcuate nuclei of the hypothalamus [88,111], and along with the inhibitory peptide, somatostatin, mediates the neuroendocrine regulation of pituitary growth hormone synthesis and secretion. GHRH is also expressed in the placenta, where it may have paracrine functions or contribute to foetal growth [81,123]; in the gonads, where it may be an autocrine or paracrine regulator of steroidogenesis and granulosa or Sertoli cell function [1,7,21]; and in lymphocytes, where it may modulate lymphocyte activation and immune function [121]. An important role for GHRH in post-embryonic growth is suggested by clinical studies with tumours that secrete GHRH [35-36], and by animal studies using transgenic mice that overexpress GHRH [57,120]. In these examples of GHRH excess, growth hormone hypersecretion, pituitary somatotroph cell hyperplasia and inappropriate patterns of growth (acromegaly or gigantism) are observed.

Growth hormone-releasing hormone is a peptide hormone of 42-44aa (depending on the species) that is proteolytically processed from a larger precursor protein of 103-108aa [37,84,123]. The GHRH precursor also encodes an additional C-terminal peptide that is reported to modulate Sertoli cell activity in the testis [9]. GHRH is structurally related to a large family of peptide hormones including secretin, glucagon, GLP-1 and GLP-2, vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide, peptides with histidine as N-terminus and isoleucine as C-terminus, and GIP [14].

The mature peptide is amidated at the C-terminus in many species, but not in rodents. Shorter processed forms of the full-length human peptide GHRH(1-44)NH₂ have been characterized, with the predominant forms being GHRH(1-40)OH in hypothalamus [76] and GHRH(1-37)NH₂ in a pancreatic tumour [51,107]. Carboxyl-terminally truncated peptides as short as GHRH(1-29)NH₂ display growth hormone-releasing activity comparable to that of the full-length peptide [1,7,9,14,21,35-37,50,57,75-76,81,84,87-88,111,119-121,123], and GHRH(1-29)NH₂ has therefore served as the template for the design of most GHRH receptor agonists and antagonists.

Several modifications to GHRH, including substitution of the conserved alanine at position 2 with other residues such as D-alanine, improve in vivo potency [70], largely by inhibition of proteolytic degradation by dipeptidylpeptidase IV, which rapidly hydrolyses the Ala²-Asp³ bond and inactivates GHRH in serum [34]. Enhancement of the amphipathic α-helical properties of GHRH by alanine replacement results in enhanced receptor affinity and increased potency in in vitro assays [18,22], and an analogue with 48% alanine content, [D-Ala², Ala^{8,9,15,16,18,22,24-28}]GHRH(1-29)NH₂ (NC-9-45) is 1.9-fold more potent than the parent compound [22]. Analogues combining the degradation stabilising replacements at position 2 with α-helix-enhancing modifications such as the Ala¹⁵ substitution have been particularly effective for increasing activity in vitro and in vivo [141].

Replacement of the conserved alanine at position 2 of GHRH with D-arginine converts the hormone into a competitive antagonist [108]. Working with this compound, a subsequent generation of potent GHRH antagonists were developed (the MZ series) containing the helix-stabilising substitutions Phe(4-Cl) at position 6, α-aminobutyric acid at position 15 and norleucine at position 27, together with a hydrophobic N-terminal acyl moiety and a C-terminal agmatine [150]. Representative examples include MZ-4-71 and MZ-5-156. The more recent series of antagonists, the JV series, incorporate arginine or homoarginine at position 9 and an enzymatically resistant C-terminal D-Arg²⁸-Har²⁹-NH₂ group [138]. Representative examples include JV-1-36 and JV-1-38. These antagonists are being developed largely as potential antitumour agents, in that they inhibit the growth of many tumour cells, probably by suppression of IGF-1 or IGF-2 production [113].

The GHRH receptor was initially cloned from human, rat and mouse pituitary, and in these species the isolated cDNAs encode a 423aa protein [43,73,83]. The porcine receptor was later identified as a 451aa protein, but it appears that there are several isoforms with differing C-termini, presumably generated by alternative RNA processing [66]. The predicted GHRH receptor protein has the seven potential membrane-spanning motifs of a G protein-coupled receptor, it is homologous to the receptors for peptides related to GHRH, it has the molecular size expected from GHRH photoaffinity cross-linking studies, and it is expressed predominantly in the anterior pituitary gland, the site of GHRH action [41,86].

When the GHRH receptor protein is expressed in transfected cells, these cells acquire the ability to bind GHRH with high affinity and selectivity and to respond to GHRH to activate adenylate cyclase and increase intracellular levels of the second messenger cAMP [24,43,60,83]. In somatotroph cells, GHRH also stimulates an influx of Ca²⁺ [63,79] most likely through voltage-sensitive Ca²⁺ channels [20]. While GHRH is reported to stimulate the PLC-IP pathway in pituitary cells in some studies [15,101], other studies report no activation of this pathway [30,33], and no coupling of the cloned receptor to this signalling pathway has yet been detected in transfected cells [89]. A recent study suggests that distinct somatotroph cell subpopulations may respond differently to GHRH with respect to activation of the phospholipid turnover signalling pathway [104].

Although the predominant site of GHRH receptor expression is the pituitary gland, the receptor mRNA has been localized to numerous other tissues, including the placenta, a site of GHRH production [85], the kidney [82,85], and the hypothalamus [125]. Using sensitive RT-PCR-Southern blotting assays, the receptor transcript has been found in an extremely wide range of rat tissues [82], although expression of the protein has not yet been demonstrated and the physiological significance of this broad expression remains unclear. Within the pituitary gland, expression is confined to the anterior lobe [73,83]. It remains uncertain whether pituitary cells other than the growth hormone-secreting somatotrophs express the GHRH receptor.

The GHRH receptor gene maps to the centromeric region of mouse chromosome 6 [45,74], and to human chromosome 7p14/15 [44,139]. The gene has been characterized in detail in the human [102], mouse [74] and rat [89], and consists of 13 major exons spanning approximately 15kb of DNA. The rat gene includes 14 exons, and exon 11 is included in an alternatively spliced variant mRNA, resulting in the insertion of 41aa into the third intracellular domain of the receptor. This variant receptor binds GHRH, but does not mediate signalling through the cAMP pathway [89]. An alternatively spliced form of the human GHRH receptor that is truncated following the fifth transmembrane domain has been identified both in normal pituitary and in pituitary adenomas [59,126], and is reported to exert a dominant inhibitory effect on signalling by the normal receptor in co-transfection experiments [95]. Alternative RNA processing probably contributes to the C-terminal heterogeneity observed for the porcine GHRH receptor [66], and for the dwarf rat GHRH receptor [151].

An inactivating mutation of the GHRH receptor was first reported in the little mouse [45,74]. This is an autosomal recessive mutation mapping to chromosome 6 that results in somatotroph hyperplasia, growth hormone deficiency, and a dwarf phenotype in the homozygous mutant animals [29]. There is a missense mutation in the GHRH receptor gene of the little mouse, resulting in replacement of the aspartic acid at position 60 in the N-terminal extracellular domain of the receptor with glycine [45,74]. This mutation does not affect the expression or cellular localisation of the mutant receptor protein, but it abolishes binding of GHRH by the mutant receptor, resulting in a loss of GHRH signalling and subsequent defects in somatotroph proliferation and function [42]. Several mutations leading to inactivation of the GHRH receptor have been reported in humans. Three distinct kindreds from India [140], Pakistan [2] and Sri Lanka [99] have been reported that have a nonsense mutation truncating the GHRH receptor at position 72 in the N-terminal extracellular domain. A Brazilian kindred has a mutation in a splice donor site that leads to retention of the first intron, a shift in the translational reading frame, and truncation of the receptor protein at position 20, near the probable signal sequence cleavage site [109].

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