There are a large number of intercellular signaling molecules which are peptides.  Many of these function in the nervous system.  In humans, their functions include the signal for the onset of childbirth, the production of milk, regulation of digestion, the perception of pain, the regulation of body lipid levels, cell growth, and blood volume.  Many of these peptide signaling molecules appeared early in animal evolution.

     E. coli synthesize a protein similar to insulin (LeRoith, 1981).and several protozoans are known to make peptides similar to adrenocorticotropic hormone, β-endorphin, and dynorphin (LeRoith, 1981).  Cnidarians  produce FMRFamide-like peptide, oxytocin/vasopressin, and other peptides (Thorndyke, ).  Cells of a sea anemome are depicted below.


Invertebrate nervous systems utilize a vast array of neuropeptides which are detected by G Protein Coupled Receptors. More than 130 neuropeptides have been identified in the nematode C.elegans along with additional putative neuropeptides. These neuropeptides can be classified in at least 11 separate families. Some families, such as the neuropeptide-like protein (nlp) family, are not yet known to have homologs in vertebrates (Nathoo, 2001). A large number of peptide signals had evolved prior to the division of the coelomate lineages.   Evidence indicates that mollusks (such as the slug in the following image) synthesize vasopressin, vasotocin, oxytocin, CRF, ACTH, αMSH, enkephalin, dynorphin, somatostatin, substance P, glucagons, insulin, secretin, gastrin, calcitonin, VIP, GIP, PP, FMRamide, AKH, dopamine, serotonin, histamine, and octopamine (Thorndyke, ).  


Insects synthesize oxytocin, vasotocin, vasopressin, neurophysin, substance P, bombesin, gastrin/CCK, VIP, PP, serotonin, and dopamine (Thorndyke, ).. Annelid worms synthesize dynorphin, and enkelpalin-like substances. Caenorhabditis elegans possesses genes for 75 peptide hormones, Drosophila melanogaster possesses 100, and some insects, such as Apis mellifera may possess 200 ( De Loof, 2008) . Vasopressin and its receptor apparently evolved in ancestral coelomates given that both are known in vertebrates, insects, annelids, and mollusks, and that it functions as an anti-diuretic in animals as diverse as humans and beetles (Hauser, 2007).

Protochordates synthesize bombesin, calcitonin, β endorphin, enkephalin, gastrin/CCK, glucagons, insulin, LHRH, motilin, αMSH, neurotensin, PP, prolactin, secretin, somatostatin, substance P, VIP, serotonin (Thorndyke, ).  Tunicates possess genes for all major peptide hormone receptors (such as insulin and gonadotropins), except growth hormone (Dehal, 2002).   




      Neuropeptide Y (NPY), gut endocrine peptide YY (PYY), pancreatic polypeptide PP (PP) and pancreatic polypeptide PY (PY) are all composed of 36 amino acids (except in chicken PYY which possesses 37).  NPY-like neuropeptides have been found in flatworms (such as the planarian in the following image), mollusks, and tapeworms (Larhammar, 1993; Hoyle, 1998). 


NPY had evolved by the appearance of jawless fish and a duplication of the NPY ancestral gene occurred before lampreys to produce NPY and PYY.  Pancreatic polypeptide arose from a gene duplication of the ancestral PYY (peptide YY) gene in the tetrapod lineage.  A duplication in some teleosts produced the neuropeptide PY.  (Youson, 1999; Larhammar, 1993). 

     All vertebrates possess neuropeptide Y in central and peripheral nervous systems (Larhammar, 1993).  The distribution of neuropeptide Y recognition sites in the brains of lungfish is similar to that observed in amphibians (Vallarino, 1998).  Mutations in the NPY gene cause the obesity in mice indicating that NPY involved in the control of lipid metabolism.  In humans, polymorphisms of this gene have been correlated to variations in serum cholesterol, LDL levels, atherosclerosis, and serum triglyceride levels.  NPY also has other roles: it is expressed in the olfactory epithelium and, in mice, affects alcohol intake.  One polymorphism in humans is observed more frequently in those who are alcohol dependent (OMIM).



PPY regulates pancreatic secretions and has a role in weight gain.  It is secreted from the endocrine tissue of the pancreas.





PYY2 is secreted from enteroendocrine cells of the pancreas and small intestine and it inhibits the activity of the stomach.  Decreased activity may be a factor in obesity.


     Seminalplasmin is the major basic protein in bull semen which regulates calcium transport and is involved in the changes to the acrosome at fertilization.  It is a member of the Neuropeptide Y gene family which has recently acquired a function unrelated to the signaling aspect of the other members of the family.

Only three amino acids are variant between shark and human NPY; it is one of the most highly conserved peptides in vertebrates (Herzog, 1995).



Growth Hormone

     Growth hormone, prolactin, and somatolactin are members of a gene family.  Growth hormone (GH) is the only member of the family known to exist in agnathans.  The secretion of growth hormone affects virtually all kinds of cells in the human body and is important for both growth early in life and normal the maintenance of tissues throughout life.Lampreys produce a GH-like molecule which is more similar to gnathostome GH than to other members of the gene family such as prolactin and somatolactin (Kawauchi, 2005). Lamprey growth hormone is organized into the same exons as GH in vertebrates, although the introns are much longer (Moriyama, 2005). While there is only a single growth hormone gene in most vertebrates, gene duplications have produced multiple copies in teleost fish, goats, and primates (the latter of which have four genes) (Chuzhanova, 2000; Sower, 2001).  While prosimians (like most mammals) possess a single growth hormone gene, multiple duplications in ancestral anthropoid primates have resulted in a cluster of growth hormone and chorionic somatomammatropin hormone genes (five to eight) in modern anthropoids (Gonzalez-Alvarez, 2006).Growth hormone genes experienced accelerated evolution following duplication in anthropoid primates (Ye, 2005).

The cells of the anterior pituitary (pictured in the following image) release growth hormone and prolactin.



     While prolactin is best known for its role in mammals in promoting milk production from mammary glands, vertebrates developed prolactin long before mammals evolved.  Prolactin is known to have more than 300 functions in vertebrates, more than the roles of all other pituitary hormones combined.  One of its major roles in fish and amphibians is the control of osmotic balance (Manzon, 2002; McCormick, 2006).While humans only possess a single prolactin gene, the mice genome possesses a cluster of 26 genes.  Twenty-one of these genes seem to encode nonclassical prolactin molecules that function without binding the prolactin receptor (Ain, 2004). Many have functions as diverse as eryhtropoeisis, differentiation of megakaryocytes, and binding to immune cells (Bittorf, 2000).

The cells of the mammalian placenta (the trophoblast) release prolactin-like protein A (PLP-A) which protects the embryo from maternal natural killer cells. More specifically, PLP-A bind natural killer cells which causes an increase in the intracellular calcium and prevents the cells from producing significant amounts of interferon (Ain, 2003). The decidual/trophoblast prolactin related protein (d/tPRP) inhibits the action of uterine eosinophils after implantation, perhaps as a mediator of progesterone (Wang, 2000).

The cells of a lactating breast are depicted below.


Somatolactin is another member in this gene family which is a recently discovered hormone in fish (Sower, 2001).

     The prolactin/growth hormone family of cytokine/circulating hormones.  In rodents, at least 15 members of this gene family, including prolactin-like protein A which is a signal sent by the embryonic trophoblast to the natural killer cells of the maternal uterine tissue (Muller, 1999a).



     Most metazoan animals use sex steroids in differentiation of male and female reproductive structures and oxytocin for the majority of the acute events that occur at these structures structures.  Oxytocin and vasopressin family members are known from 4 invertebrate phyla and all groups of vertebrates (Youson, 1999).  Cnidarians produce oxytocin/vasopressin (Thorndyke, ).  A number of peptides similar to oxytocin/vasotocin are known in invertebrates such as Arg-conopressin-S in mollusks, Lys-conopressin-G in mollusks, cephalotocin in mollusks, annetocin in annelids, Lom-DH in arthropods, and Stp-OLP in tunicates.  Mollusk conopressin genes are homologous to those of vasoticn/oxytocin in vertebrtates (Hoyle, 1998; Youson, 1999; Kesteren, 1992).    In worms, annetocin functions in egg-laying and the contraction of neprhidia (which propel both wastes and gametes) (Ivell, 1999). Arginine vasotocin/vasopressin functions in water retention in jawed vertebrates (McCormick, 2006).

    The neurohypophysial hormones of vertebrates are divided into two groups: oxytocin and vasotocin families.  Lungfish have the same oxytocin family member, mesotocin, found in amphibians, reptiles, and birds as opposed to the isotocin found in teleost fish (such as the teleost hatchling pictured below).  The vasotocin family member in lungfish, copeptin, has two regions which are shared with amphibians rather than with teleost fish (Hyodo, 1997).

.  Oxytocin functions in a paracrine hormone in mammals, being produced in the hypothalamus, pituitutary, mammary gland, ovary, uterus, testis, and prostate.  Oxytocin functions as an endocrine hormone initiating the events of childbirth and milk ejection.  In ruminant mammals, oxytocin is secreted from the ovary to induce luteolysis and in induces the formation of the corpus luteum in marmosets.  The processes regulated by oxytocin tend to utilize positive feedback mechanisms (such as in birth, milk ejection mediated by neurons followed by recovery, and in the deterioration of the corpus luteum, (Ivell, 1999). The cells of the posterior pituitary (which secrete oxytocin) are depicted in the following image.

     The single amino acid mutation in ancestral vasotocin which gave rise to vasopressin seems to have occurred only in the ancestral mammals.  All non-mammalian vertebrates possess vasotocin (Hoyle, 1998). Oxytocin has been linked to both increased social interaction in non-human animals and to increased trust in human social behaviors (Kosfeld, 2005). Oxytocin functions in olfactory recognition of offspring and forming pair bonds in females. In males, pair bond formation seems to be linked to arginine vasopressin (Curley, 2005).

In addition to the release of oxytocin into the bloodstream, neurons send oxytocin from paraventricular nuclei to a variety of sites such as hypothalamus, amygdala, and hippocampus (Lehto, 2007). Oxytocin is associated with love and trust (Lehto, 2007).


     Substance P, tachykinins, and neurokinins are members of a gene family.  No known invertebrate peptides are known which belong to this family (Hoyle, 1998).

Neurokinin A is known in all tetrapods. (Hoyle, 1998).  Frogs possess additional kinin molecules. Substance P is related to kinins and is known in amphibians and sharks (Hoyle, 1998).  Mammals are known to possess several members of a tachykinin family including substance P, neuromedin K and neuromedin L.  Other tachykinins are known in amphibians (Kozawa, 1991). 


     In mammals, the preprotachykinin genes can encode one or more tachykinins. The α-PPT-A gene encodes Substance P.  The β-PPT-A gene encodes substance P, neurokinin A, and neuropeptide K.  The γ-PPT-A gene encodes substance P, neurokinin A and neuropeptide γ.  The PPT-B gene encodes neurokinin B (Otsuka, 1993; Hoyle, 1998).  Tachykinin effects are mediated through three NK receptors which are G protein coupled receptors (Otsuka, 1993).



     Tachykinins are known in both vertebrates and invertebrates.  Humans have 2 tachykinin genes.  TAC1 is the precursor gene for two peptides, substance P and neurokinin A which are involved in pain responses.  They are released from pain receptors after moderate to intense pain stimuli.  Substance P may also be a vascular growth factor. 



The TAC3 gene encodes neurokinin B which is secreted from the placenta and can affect maternal hypertension.  Substance P and neurokinin A are released produced in and released by neurons, may be considered neurotransmitters (Otsuka, 1993).



The gene TAC4  encodes 4 peptide endokinins (endokinins A through D).  Endokinins A and B are similar in function to substance P.



Oculomedin is a peptide similar to tachykinins produced in the retina.

The following image is of a developing eye in a pig embryo.



The genes for the family of CRF peptides (corticotrophin-releasing factor 1, CRF2, stresscopin/urocortin III, stresscortin-related peptide/urocortin II) which determine vertebrate stress responses arose from duplications early in the history of vertebrates.  Although the use of corticotropin releasing factor (CRF) as part of the hypothalamic-pituitary-adrenal axis is specific to chordates, the hormone CRF and some of its roles (such as those in feeding) evolved in ancestral coelomates (Lovejoy, 2006). This family is in turn related to the calcitonin family of peptides (Chang, 2004).  The receptors for the stress response CRF (corticotrophin-releasing factor) family of peptides are GPCRs which are related to insect diuretic hormone receptors (Chang, 2004).




Urocortin is a CRF (corticotropin-releasing factor)-like peptide in the brain which mediates the effects of stress on appetite.



Stresscopin is secreted to mediate the stress response.



Stresscopin-related peptide is also involved in stress responses and is released from in the CNS and periphery.



The hypothalamus releases this hormone with stress.  It is involved in measuring the length of pregnancy and helps to trigger birth.  Its levels affect depression.



Opioids are signals which function in pain stimuli, feeding, sexual behavior, learning, thermoregulation, development, and the physiology of the cardiovascular and respiratory systems.  The opioid met-enkalphin promotes cell proliferation in several bacteria and protists which possess opioid receptors (Zagon, 1992; Danielson, 1999).  Opioid-like peptides known from arthropods, mollusks, and annelids.  Pordynorphin and large peptide precursors of opiates seem to exist in mollusks (Stefano, 1998).

     Enkalphin and POMC are known in several non-amniotes, including aganthans.  The duplication of the ancestral gene preceded craniates.  Proorphanin seems to have resulted from an early duplication of the gene for proenkalphin in gnathostomes.  Another duplication of the proenkalphin gene produced prodynorphin in the lineage which produced sarcopterygians and tetrapods (Danielson, 1999).  The skin of amphibians can possess a number of opioids which act on μ and δ opioid receptors (Schmidt, 1997).



The PNOC gene produces two neuropeptides, nociceptin and nocistatin which are both involved in pain pathways.  Nociceptin may also be involved in memory formation.



Enkalphin is produced in the brain and adrenal glands and is involved in responses to pain and stress and in aggression.



This gene encodes the neuropeptidedes neoendorphin, dynorphin, and leumorphin.



The POMC gene encodes a number of signal molecules: ACTH (which stimulates secretion of hormones from the adrenal cortex), a MSH, bMSH, g MSH (which affect melanocytes and pigmentation), b lipotropin, g lipotropin, corticotropin-like intermediate lobe peptide (CLIP), and b endorphin.  In humans, mutations have been shown to cause obesity, red hair, and adrenal insufficiency (OMIM).  Unlike jawed veretebrates which possess one single gene POMC, lampreys encode a POM gene encoding two MSH peptides and βEND and a POM gene encoding ACTH and a different βEND (Kawauchi, 2005).The lungfish POMC gene possesses a g-MSH sequence like the gene in tetrapods and unlike the gene in other fish (Lee, 1999).  The distribution of a-MSH recognition sites in the brains of lungfish is similar to that observed in amphibians (Vallarino, 1998).    The N-acetylation of a-MSH and b-endorphin occurs before they are secreted in bony fish and mammals (Dores, 1994).   Some cartilaginous fish possess a dMSH sequence in the POMC gene (Alrubaian, 2003).



The secretin family includes glucagons, glucagon-like peptides, gastric inhibitory peptide, secretin, enteroglucagon, vasoactive intestinal peptide, and GHRH (Nelson, 2006).


This gene affects epinephrine secretion, smell, and learning and was first identified in the hypothalamus.  Homologs exist in Drosophila.



VIP is expressed in nervous and gastrointestinal tissues.  It is antinflammatory and affects immune reactions. VIP functions in salt secretion in jawed vertebrates (McCormick, 2006).



GHRH is produced by the hypothalamus to affect the secretion of growth hormone from the pituitary.  It is also a paracrine/autocrine hormone produced by the lung and gastrointestinal tract (the latter is pictured below). GHRH and its receptors are known in bony fish and tetrapods (Lee, 2007).



NXPH1 is expressed in the spleen, but not in the CNS.  Cells of the spleen are pictured below.





NXPH3 is specific to the brain.



NXPH3 is expressed in the brain, spleen, and testis.



The peptide hormone urotensin consistes of 12 amino acids in fish, 13 in amphibians, and 11 in humans and the biologically active cycle region in conserved in all.   This peptide was long thought to be present only in fish.  Urotensin  II-like peptides are also known in mollusks (Coulouarn, 1998).



Urotensin 2 is a vasoactive factor and affects calcium flow in the heart and heart size.  It has been conserved from fish through humans and there are urotensin 2-like peptides known in invertebrates. 



The pituitary adenylate cyclase activating peptide (PACAP) is a member of the glucagon/secretin/VIP family which functions in the differentiation, division, and survival of both neural and nonneural cells, including the sensory neurons of the dorsal root ganglion (Nielson, 2004). 



Leptin is homologous to the gene product of the obese gene in mice.  Leptin levels in infants are correlated with birth weight.  It is secreted by adipose and the placenta.  Lower levels of leptin are correlated with the risk of obesity, lower metabolism, and may cause underdevelopment of the gonads.  Increased levels may increase the risk of prostate cancer.  Leptin has a number of functions in addition to nutrient balance (such as inflammation, development, and other physiological reactions). It is known in amphibians (Boswell, 2006).

Leptin may be one of the signals involved in the onset of puberty.  Human adipose tissue is depicted below.



Ghrelin increases the release of growth hormone and stimulates the neurons in the hypothalamus which release NPY.  It is secreted by the stomach to act on the pituitary.  Mutations in humans contribute to obesity.



GRP is the homolog of the amphibian hormone bombesin. It is secreted from neuroendocrine cells of the lung to increase gastrin secretion and control glucagon concentrations.



PMCH is produced in the mammalian hypothalamus and the salmon pituitary.  It is involved in the regulation of food intake, general cerebral activity, and weight gain.  This gene encodes MCH and two other neuropeptides, NEI and NGE.



The glucagon family of peptides includes secretin, VIP, GIP, and glicentin.  The glucagon gene encodes glucagon, glucagon-like peptide 1, and glucagon-like peptide 2.  Glucagon is secreted by the pancreas to raise blood glucose levels while the second two are secreted from the gut and affect glucose transport in the intestine, intestinal inflammation, and satiety.



Secretin is produced by cells of the proximal small intestine to stimulate the production of pancreatic juices and bile. Two neuropeptides, named hypocretins, have been identified which are similar to secretin and are expressed specifically in the hypothalamus (De Lecea, 1998).



Gastric inhibitory peptide inhibits the activity of the stomach.




GnRH genes are not part of a larger gene family (Fernald, 1999).  GnRH is known in a number of mollusks where it is affects neural function and gonadal function (Zhang, 2000a).GnRH in tunicates not only is capable of stimulating gamete development and steroid hormone production in the tunicate gonads, it can also stimulate the secretion of LH from a mammalian gonad (Di Fiore, 2000).There are three GnRH genes known which appear to have resulted from an ancestral gene which was duplicated in ancestral vertebrates.  Two of the three resulting decapeptides have the same amino acid sequence in all known species.  Basal actinopterygians, lungfish, amphibians, marsupials, and primitive placental mammals possess two GnRH genes.

Echinoderms utilize a number of neuropeptides including GnRH (Rowe, 2007). Tunicates possess four major neurohormones: GnRH, insulin, insulin-like growth factor, and cionin (which may be the ancestral hormone of both CCK and gastrin). Tunicates lack a pituitary gland and the hormones FSH and LH and evidence indicates that GnRH directly affects gonads and other tissues. In addition to its role in the digestive tract, CCK affects mammalian memory, sleep, sexual activity, and emotions. Gastrin also is expressed in mammalian brains (Sherwood, 2005).

GnRH3 is known only in fish to date (Fernald, 1999; King, 1995).

     In humans, GnRH1 is produced in the spleen, lymphocytes, liver, muscle, kidney, placenta.  Expression is also widespread in fish.  GnRH2 is expressed in the human brain, prostate, bone marrow, and kidney.  The terminal nerves in many fish release GnRH and lesions of these neurons interferes with specific aspects of male reproductive behavior.  There is one report of abnormal reproductive behavior after terminal nerve damage in mammals (Yamamoto, 1997).

     In Kallman’s syndrome, patients are unable to smell and they possess underdeveloped gonads.  In these patients, the embryonic GnRH secreting cells fail to migrate from the olfactory bulb to the hypothalamus (Hohl, 2001).

 FSH and LH

The structure of lamprey GTH is homologous to TSH, LH, and FSH in gnathostomes but shows significant sequence differences (Kawauchi, 2005). While gnathostomes possess two gonadotropins, FSH and LH, lampreys possess only one, GTHβ-like, which is intermediate between FSH and LH (Sower, 2006).


--NPFF affects blood pressure and pancreatic secretions. The neuropeptide FF is known throughout vertebrates, beginning with lampreys. Its distribution in the brain is comparable in lampreys and mammals (Pombal, 2005).



NPFF1 is produced in the septum, thalamus, and superior colliculus.



FMRF-amide is a neuropeptide shared by both vertebrates and invertebrates (Vallarino, 1998).   Cnidarians  produce an FMRFamide-like peptide (Thorndyke, ). The distribution of FMRF-amide in lungfish brains is more similar to amphibians than other fish (Vallarino, 1998). 



Cholecystokinin (CCK) and gastrin are peptide hormones involved in digestion.  The protochordate Ciona has a single peptide of this gene family from which CCK and gastrin are thought to have evolved.  Since cartilaginous fish and higher vertebrates possess both CCK and gastrin, the divergence of these homologous genes occurred before the origin of cartilaginous fish (Johnsen, 1997; Johnsen, 1996). 



The response of the cells of the bowfin aorta to bradykinin is comparable to those of mammals.  There is only one amino acid difference between the forms of bradykinin in humans and bowfins (Conlon, 1995).



NPB is expressed in the CNS and other tissues.



NPW is expressed in the substancia nigra and other tissues.


The somatostatin family (including insulin) must be modified from a precursor form before the hormone is functional (Nelson, 2006).


Somatostatin is expressed in the central nervous system, pancreas, intestine, and stomach where it functions as a hormone or neuromodulator.  The amino acid sequence is identical from jawless fish through mammals.  A second somatostatin gene (termed cortistatin in mammals) is known in actinopterygians, sarcopterygians, amphibians, and mammals (Trabucchi, 1999).



Corticostatin is similar to somatostatin and affects sleep patterns.



Galanin is expressed in the hypothalamus where it stimualates LH secretion.  It also affects the gastrointestinal tract.  In humans, mutations can affect stature, overall development, obesity, and the development of the reproductive system.  It is neuropeptide known from gnathostome vertebrates (OMIM).





Parthyroid hormone-related protein (PTHrP)

     Parthyroid hormone-related protein (PTHrP) is a paracrine hormone in amniotes but endocrine actions are known in fish.  It’s a large gene with 9 exons spread over 1.5 kb of DNA.  Like parathormone, PTHrP is involved in calcium metabolism but it is involved in many other functions as well such as smooth muscle tone and differentiation.  Parathyroid gland evolved in tetrapods although some amphibians use pituitary to control high concentrations of calcium (Ingleton, 1996). PTH-like proteins in fish before the parathyroid gland evolved.  PTHrP known from brain of cartilaginous fish (Ingleton, 1996).  Cells of the parathyroid are depicted in the following image.



The calcitonin gene family includes calcitonin, CGRP, amylin, adrenomedullin, and intermedin.  The duplication of ancestral genes occurred in ancestral jawed vertebrates and the subsequent genome duplication in teleosts created multiple copies of some mammalian genes (Chang, 2004).


The calcitonin gene can be spliced to make two gene products: calcitonin and calcitonin-gene related peptide (CGRP). CGRP is known in coelomates while calcitonin is only known in vertebrates. Mammals possess a second calcitonin gene which only produces CGRP. In vertebrates, calcitonin is produced in the thyroid while CGRP is produced in nerves (Lafont, 2007). In invertebrates, CGRP is involved in osmotic balance and calcium metabolism, as is calcitonin in vertebrates. In mammals, CGRP only affects calcium balance at levels above normal physiological levels (Lafont, 2007).


Adrenomedullin affects blood pressure in humans and abnormal levels can cause hypertension, kidney failure, and spontaneous abortion.


Amylin is secreted by pancreatic β cells and acts on bones and blood vessels.

Intermedin lowers blood pressure (Chang, 2004).


     Tetrapods possess 3 natriuretic peptides (atrial natriuretic peptide, B-type NP, and C-type NP).  These multiple genes resulted from duplications early in the vertebrate lineage from the ancestral condition of one single gene (as in hagfish) (Inoue, 2003).  Natriuretic peptide functions in salt balance in jawed vertebrates (McCormick, 2006). Jawless fish and sharks possess a single natriuretic peptide gene. A number (perhaps seven) have been identified in bony fish. Tetrapods possess three peptides: ANP, BNP, and CNP ( Ventura, 2006).

Angiotensin II functions in the regulation of fluid volume in jawed vertebrates (McCormick, 2006).