Structure
β-END is derived from the C-terminal region of the
common precursor POMC. It is composed of 31 aa residues in mammals. The N-terminal 5 aa
sequence, Tyr-Gly-Gly-Phe-Met, is identical to Metenkephalin, which is derived from proenkephalin, and
is essential for analgesic activity. Acetylation occurs at
the N-terminal tyrosine in a substantial amount of
β-END in the pars intermedia. Nonacetylated β-END is
the active form, and acetylated β-END is the inactive
form. α-END and γ-END correspond to β-END(1–16)
and β-END(1–17), respectively. In the frog Xenopus laevis, N-acetyl-β-END(1–8) has been shown to be the terminal product of β-END processing. The N-terminal 5 aa
sequence sometimes undergoes mutation in species having two or more pomc genes. In the barfin flounder, in
which three POMC sequences have been reported, Tyr-Gly-Gly-Phe-Met is changed to Ser-Gly-Arg-Phe-Met. In lampreys, one of the two POMCs (arbitrarily termed
proopiomelanocortin, POM), which is synthesized in
the pars intermedia, could be a source of Met-enkephalin.
The Met-enkephalin sequence is segregated with basic
amino acids from the rest of the β-END sequence consisting of the 28-aa identification of β-END(8–35), suggesting
the liberation of the Met-enkephalin sequence.
Receptors
β-END and a related peptide such as β-END(1–27) are
agonists for the μ-opioid receptor (MOR), although these
peptides also bind to the δ-opioid receptor with slightly
weaker affinities. MOR is a subtype of opioid receptor
belonging to the GPCR superfamily. The location of
MOR in human chromosomes is 6q24–q25.
Agonists and Antagonists
DAMGO, sufentanil, hydromorphone, fentanyl, and
nalbuphine are agonists. Naloxone, naltrexone, nalmefene, alvimopan, and
levallorphan are antagonists.
Biological functions
β-END exhibits opiate-like analgesic activity that is
18–33 times more potent than that of morphine, and its
actions are blocked by the specific opiate antagonist naloxone hydrochloride. It also affects feeding, sexual
behavior, and learning, and modulates neuroendocrine
function when administered into the cerebral ventricle
or the brain. In peripheral tissues, β-END is associated
with the cardiovascular and immune systems, although
the significance of peripherally circulating β-END
remains to be fully elucidated. N-Acetylated forms of
β-END do not bind to opioid receptors. MOR, DOR,
and KOR are expressed in goldfish interrenal cells, where
β-END suppresses the basal release of cortisol and
inhibits the cortisol-releasing activity of ACTH. N-Acetylated forms of β-END have no effect on cortisol
release. In mammals, the effects of β-END on
coticosteroidogenesis are inconsistent, depending on
the dose, the functional state of the adrenocortical cells,
and the properties of animals used for investigations. In amphibians, β-END inhibits corticosteroid secretion
from interrenal tissue. Additionally, β-END is associated with food intake and the immune system in
fish.
Description
Endorphin is an endogenous morphine secreted from the
pituitary. Sources are corticotropes in the pars distalis and
melanotropes in the pars intermedia. The fact that END is derived from a precursor protein
called proopiomelanocortin (POMC) was demonstrated
in 1979 using the pars intermedia in the bovine
pituitary.
Clinical Use
There is a correlation between endogenous opioid peptides, especially β-END, and alcohol abuse. The consumption of alcohol activates the endogenous opioid
system. The consumption of alcohol results in an increase
in β-END levels in the brain regions that are associated
with reward. However, it has also been observed that
habitual alcohol consumption leads to β-END deficiency.
People with a genetic deficit in β-END are particularly
susceptible to alcoholism. The plasma levels of β-END
in subjects genetically at high risk of excessive alcohol
consumption show lower basal activity of β-END. Recently, β-END has been shown to play a role in the
pathophysiology of major depressive disorder in
addition to a variety of physiological functions such as
cardiovascular regulation and several kinds of behavior
and stress responses.
