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| Names | |
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| IUPAC name L-Tyrosylglycylglycyl-L-phenylalanyl-L-methionyl-L-threonyl-L-seryl-L-glutaminyl-L-lysyl-L-seryl-L-glutaminyl-L-threonyl-L-prolyl-L-leucyl-L-valyl-L-threonyl-L-leucyl-L-phenylalanyl-L-lysyl-L-asparaginyl-L-alanyl-L-isoleucyl-L-isoleucyl-L-lysyl-L-asparaginyl-L-alanyl-L-tyrosyl-L-lysyl-L-lysylglycyl-L-glutamine | |
| Identifiers | |
3D model (JSmol) | |
| ChEBI | |
| ChemSpider | |
| ECHA InfoCard | 100.056.646 |
| UNII | |
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| Properties | |
| C158H251N39O46S | |
| Molar mass | 3465.03 g·mol−1 |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
β-Endorphin (beta-endorphin) is anendogenousopioidneuropeptide andpeptide hormone that is produced in certainneurons within thecentral nervous system andperipheral nervous system.[1] It is one of threeendorphins that are produced in humans, the others beingα-endorphin andγ-endorphin.[2]
There are multiple forms of β-endorphins with the full sequence ofTyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu-Phe-Lys-Asn-Ala-Ile-Ile-Lys-Asn-Ala-Tyr-Lys-Lys-Gly-Glu (31 amino acids) denoted as β-endorphin(1-31) and variants truncated to the first 26 and 27 amino acids as β-endorphin(1-26) and β-endorphin(1-27).[1][3][4] However, β-endorphin(1-31) is the only form that possess a potent analgesic effect and it is the primary form located in the anterior pituitary gland, and regions such as the hypothalamus, midbrain, and amygdala.[5] The first 16 amino acids are identical to α-endorphin. β-Endorphin is considered to be a part of theendogenous opioid andendorphin classes of neuropeptides;[1] all of the established endogenous opioid peptides contain the same N-terminal amino acid sequence, Tyr-Gly-Gly-Phe, followed by either-Met or-Leu.[1]
Function of β-endorphin has been known to be associated withhunger, thrill,pain, maternal care, sexual behavior, andreward cognition. In the broadest sense, β-endorphin is primarily utilized in the body to reduce stress and maintain homeostasis. In behavioral research, studies have shown that β-endorphin is released viavolume transmission into theventricular system in response to a variety of stimuli, andnovel stimuli in particular.[6]
β-Endorphin is found in neurons of thehypothalamus, as well as thepituitary gland. It is derived fromβ-lipotropin, which is produced in thepituitary gland from a larger peptide precursor,proopiomelanocortin (POMC).[7] POMC is cleaved into two neuropeptides,adrenocorticotropic hormone (ACTH) and β-lipotropin.[8] The formation of β-endorphin is then the result of cleavage of the C-terminal region of β-lipotropin, producing a 31 amino acid-long neuropeptide with an alpha-helical secondary structure. However, POMC also gives rise to other peptide hormones, including α- and γ-melanocyte-stimulating hormone (MSH), resulting from intracellular processing by internal enzymes known asprohormone convertases.
A significant factor that differentiates β-endorphin from other endogenous opioids is itshigh affinity for and lasting effect onμ-opioid receptors.[7] The structure of β-endorphin in part accounts for this through its resistance toproteolytic enzymes, as its secondary structure makes it less vulnerable to degradation.[7]
β-Endorphin function is said to be divided into two main categories: local function and global function. Global function of β-endorphin is related to decreasing bodily stress and maintaining homeostasis resulting in pain management, reward effects, and behavioral stability. β-Endorphin in global pathways diffuse to different parts of the body through cerebral spinal fluid in the spinal cord, allowing for β-endorphin release to affect the peripheral nervous system. Localized function of β-endorphin results in release of β-endorphin in different brain regions such as the amygdala or the hypothalamus.[6] The two main methods by which β-endorphin is utilized in the body are peripheral hormonal action[9] and neuroregulation. It is considered to act both as aneurotransmitter and aneuromodulator since it produces effects on distant targets that have increased stability and longevity when compared to other neurotransmitters.[5] β-endorphin and otherenkephalins are often released withACTH to modulate hormone system functioning. Neuroregulation by β-endorphin occurs through interference with the function of another neuropeptide, either by direct inhibition of neuropeptide release or induction of a signaling cascade that reduces a neuropeptide's effects.[8]
β-Endorphin is an agonist of theopioid receptors; it preferentially binds to theμ-opioid receptor.[1] Evidence suggests that it serves as a primary endogenousligand for theμ-opioid receptor,[1][10] the same receptor to which the chemicals extracted fromopium, such asmorphine, derive theiranalgesic properties. β-Endorphin has the highest binding affinity of any endogenous opioid for the μ-opioid receptor.[1][7][10] Opioid receptors are a class ofG-protein coupled receptors, such that when β-endorphin or another opioid binds, a signaling cascade is induced in the cell.[11] Acetylation of the N-terminus of β-endorphin, however, inactivates the neuropeptide, preventing it from binding to its receptor.[7] The opioid receptors are distributed throughout the central nervous system and within the peripheral tissue of neural and non-neural origin. They are also located in high concentrations in theperiaqueductal gray,locus coeruleus, and therostral ventromedial medulla.[12] In addition to the full-length peptide, brain and pituitary tissue also contain shorter β-endorphin fragments such as β-endorphin(1–27), which can act as a competitive antagonist at μ-opioid receptors and attenuate the analgesic effects of β-endorphin(1–31) in experimental models.[13]
Voltage-dependent calcium channels (VDCCs) are important membrane proteins that mediate the depolarization of neurons, and play a major role in promoting the release of neurotransmitters. When endorphin molecules bind to opioid receptors, G proteins activate and dissociate into their constituent Gα and Gβγ sub-units. The Gβγ sub-unit binds to the intracellular loop between the two trans-membrane helices of the VDCC. When the sub-unit binds to the voltage-dependent calcium channel, it produces a voltage-dependent block, which inhibits the channel, preventing the flow of calcium ions into the neuron. Embedded in the cell membrane is also theG protein-coupled inwardly-rectifying potassium channel. When a Gβγ or Gα(GTP) molecule binds to the C-terminus of the potassium channel, it becomes active, and potassium ions are pumped out of the neuron.[14][15] The activation of the potassium channel and subsequent deactivation of the calcium channel causes membranehyperpolarization. This is when there is a change in the membrane's potential, so that it becomes more negative. The reduction in calcium ions causes a reduction of neurotransmitter release because calcium is essential for this event to occur.[16] This means that neurotransmitters such asglutamate andsubstance P cannot be released from the presynaptic terminal of the neurons. Substance P is a believed to help sensitize postsynaptic neurons to glutamate, aiding in the transmission of pain signals from periphery nerves to the brain.[17] These neurotransmitters are vital in the transmission of pain, and as β-Endorphin reduces the release of these substances, there is a strong analgesic effect.
β-Endorphin has been primarily studied for its influence onnociception (i.e.,pain perception). β-endorphin modulates pain perception both in thecentral nervous system and theperipheral nervous system. When pain is perceived, pain receptors (nociceptors) send signals to the dorsal horn of thespinal cord and then up to thehypothalamus through the release of aneuropeptide calledsubstance P.[8][6][18][19] In theperipheral nervous system, this signal causes the recruitment ofT-lymphocytes, white blood cells of the immune system, to the area where pain was perceived.[19] T-lymphocytes release β-endorphin in this localized region, allowing it to bind to opioid receptors, causing direct inhibition of substance P.[19][20] In thecentral nervous system, β-endorphin binds to opioid receptors in the dorsal root and inhibits the release of substance P in the spinal cord, reducing the number of excitatory pain signals sent to the brain.[19][18] The hypothalamus responds to the pain signal by releasing β-endorphin through theperiaqueductal grey network, which mainly acts to inhibit the release ofGABA, aneurotransmitter which prevents the release ofdopamine.[8][18] Thus, the inhibition of GABA release by β-endorphin allows for a greater release of dopamine, in part contributing to the analgesic effect of β-endorphin.[8][18] The combination of these pathways reduces pain sensation, allowing for the body to stop a pain impulse once it has been sent.
Immune-derived β-endorphin reduces pro-inflammatory cytokines such as IL-1 and IL-6 while increasing IL-10 and interferon-γ, contributing to systemic anti-inflammatory effects.[21]
β-Endorphin has approximately 18 to 33 times the analgesic potency ofmorphine,[22] though its hormonal effect is species dependent.[9] A comparative study found that patients with chronic neuropathic pain had significantly lower cerebrospinal-fluid β-endorphin concentrations than healthy controls.[23]
β-Endorphin release in response to exercise has been known and studied since at least the 1980s.[24] Studies have demonstrated that serum concentrations of endogenous opioids, in particular β-endorphin andβ-lipotropin, increase in response to both acute exercise and training.[24] The release of β-endorphin during exercise is associated with a phenomenon colloquially known in popular culture as arunner's high.[25] Acute aerobic exercise significantly increases circulating β-endorphin concentrations, with elevations closely correlated to exercise intensity and the onset of the 'runner’s high'.[26]
There is evidence that β-endorphin is released in response toultraviolet radiation, either through sun exposure or artificial tanning.[27] This is thought to contribute toaddiction behavior among excessivesunbathers and users ofartificial tanning despite health risks.
Studies suggest that β-Endorphins could be correlated withalcohol addiction due to their involvement with the brain'smesolimbic reward system.[28] Alcohol consumption causes an increase in the release of β-Endorphins within the regions of the brain's reward system. Regular and long-term consumption of alcohol consequently leads to a deficit in the levels of β-Endorphins that requires continuous consumption of alcohol to replenish. Individuals with a deficiency of β-Endorphins due to genetics may be more vulnerable to alcohol addiction as a result.[29]
β-Endorphin acts as an agonist that binds to various types ofG protein–coupled receptors (GPCRs), most notably to the mu and kappa opioid receptors. Binding to these receptors prevents the release of Substance P in the case of theperipheral nervous system, and the inhibitory neurotransmitter, GABA, in thecentral nervous system[30] The receptors are responsible for supra-spinal analgesia.[medical citation needed] Radiotracer studies show that circulating β-endorphin is not transported across the blood–brain barrier and is rapidly degraded by endothelial peptidases.[31]
β-Endorphin was discovered in camel pituitary extracts by C.H. Li and David Chung.[32] The primary structure of β-endorphin was unknowingly determined 10 years earlier, when Li and colleagues analyzed the sequence of another neuropeptide produced in the pituitary gland,γ-lipotropin. They noticed that the C-terminus region of this neuropeptide was similar to that of someenkephalins, suggesting that it may have a similar function to these neuropeptides. The C-terminal sequence of γ-lipotropin turned out to be the primary sequence of the β-endorphin.[7]
Opioid Peptides
β-Endorphin (also a pituitary hormone) ...
Opioid peptides are encoded by three distinct genes. These precursors include POMC, from which the opioid peptide β-endorphin and several nonopioid peptides are derived, as discussed earlier; proenkephalin, from which met-enkephalin and leu-enkephalin are derived; and prodynorphin, which is the precursor of dynorphin and related peptides. Although they come from different precursors, opioid peptides share significant amino acid sequence identity. Specifically, all of the well-validated endogenous opioids contain the same four N-terminal amino acids (Tyr-Gly-Gly-Phe), followed by either Met or Leu ... Among endogenous opioid peptides, β-endorphin binds preferentially to μ receptors. ... Shared opioid peptide sequences. Although they vary in length from as few as five amino acids (enkephalins) to as many as 31 (β-endorphin), the endogenous opioid peptides shown here contain a shared N-terminal sequence followed by either Met or Leu.
Principal endogenous agonists (Human)
β-endorphin (POMC, P01189), [Met]enkephalin (PENK, P01210), [Leu]enkephalin (PENK, P01210) ...
Comments: β-Endorphin is the highest potency endogenous ligand
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