Ghrelin, the "hunger hormone" known as lenomorelin, is a peptide hormone produced by ghrelinergic cells in the gastrointestinal tract that functions as a neuropeptide in the central nervous system. Besides regulating appetite, ghrelin plays a significant role in regulating energy homeostasis; when the stomach is empty, ghrelin is secreted. When the stomach is stretched, secretion stops.a It acts on hypothalamic brain cells both to increase hunger, to increase gastric acid secretion and gastrointestinal motility to prepare the body for food intake. The receptor for ghrelin, the ghrelin/growth hormone secretagogue receptor, is found on the same cells in the brain as the receptor for leptin, the satiety hormone that has opposite effects from ghrelin. Ghrelin plays an important role in regulating reward perception in dopamine neurons that link the ventral tegmental area to the nucleus accumbens through its colocalized receptors and interaction with dopamine and acetylcholine. Ghrelin is encoded by the GHRL gene and is produced from the cleavage of the prepropeptide ghrelin/obestatin.
Full-length preproghrelin is homologous to promotilin and both are members of the motilin family. Unlike the case of many other endogenous peptides, ghrelin is able to cross the blood-brain-barrier, giving exogenously-administered ghrelin unique clinical potential. Ghrelin was discovered after the ghrelin receptor was discovered in 1996 and was reported in 1999; the hormone name is based on its role as a growth hormone-releasing peptide, with reference to the Proto-Indo-European root gʰre-, meaning "to grow". The GHRL gene produces mRNA. Five products arise: the first is the 117-amino acid preproghrelin.. It is cleaved to produce proghrelin, cleaved to produce a 28-amino acid ghrelin and C-ghrelin. Obestatin is presumed to be cleaved from C-ghrelin. Ghrelin only becomes active when caprylic acid is linked posttranslationally to serine at the 3-position by the enzyme ghrelin O-acyltransferase, it is located on the cell membrane of ghrelin cells in the pancreas. The non-octanoylated form is desacyl ghrelin.
It does not activate the GHS-R receptor but does have other effects: cardiac, anti-ghrelin, appetite stimulation, inhibition of hepatic glucose output Side-chains other than octanoyl have been observed: these can trigger the ghrelin receptor. In particular, decanoyl ghrelin has been found to constitute a significant portion of circulating ghrelin in mice, but as of 2011 its presence in humans has not been established; the ghrelin cell is known as an A-like cell, X-cell, X/A-like cell, Epsilon cell, P/D sub 1 cell and Gr cell. Ghrelin cells are found in the stomach and duodenum, but in the jejunum, pancreatic islets, adrenal cortex and kidney, it has been shown that ghrelin is produced locally in the brain Ghrelin cells are found in oxyntic glands, pyloric glands, small intestine. They are ovoid cells with granules, they have gastrin receptors. Some produce nesfatin-1. Ghrelin cells are not terminally differentiated in the pancreas: they are progenitor cells that can give rise to A-cells, PP cells and Beta-cells there.
Ghrelin is a participant in regulating the complex process of energy homeostasis which adjusts both energy input – by adjusting hunger signals – and energy output – by adjusting the proportion of energy going to ATP production, fat storage, glycogen storage, short-term heat loss. The net result of these processes is reflected in body weight, is under continuous monitoring and adjustment based on metabolic signals and needs. At any given moment in time, it may be in disequilibrium. Gastric-brain communication is an essential part of energy homeostasis, several communication pathways are probable, including the gastric intracellular mTOR/S6K1 pathway mediating the interaction among ghrelin and endocannabinoid gastric systems, both afferent and efferent vagal signals. Ghrelin and synthetic ghrelin mimetics increase body weight and fat mass by triggering receptors in the arcuate nucleus that include the orexigenic neuropeptide Y and agouti-related protein neurons. Ghrelin-responsiveness of these neurons is both leptin- and insulin-sensitive.
Ghrelin reduces the mechanosensitivity of gastric vagal afferents, so they are less sensitive to gastric distension. In addition to its function in energy homeostasis, ghrelin activates the cholinergic–dopaminergic reward link in inputs to the ventral tegmental area and in the mesolimbic pathway, a circuit that communicates the hedonic and reinforcing aspects of natural rewards, such as food and addictive drugs such as ethanol. Ghrelin receptors are located on neurons in this circuit. Hypothalamic ghrelin signalling is required for reward from palatable/rewarding foods. Ghrelin has been linked to inducing feeding behaviors. Circulating ghrelin levels are the highest right before the lowest right after. Injections of ghrelin in both humans and rats have been shown to increase food intake in a dose-dependent manner. So the more ghrelin, injected the more food, consumed. However, ghrelin does not increase meal size, only meal number. Ghrelin injections increase an animal's motivation to seek out food, behaviors including increased sniffing, foraging for food, hoardi
Peptides are short chains of amino acid monomers linked by peptide bonds. The covalent chemical bonds are formed when the carboxyl group of one amino acid reacts with the amino group of another; the shortest peptides are dipeptides, consisting of 2 amino acids joined by a single peptide bond, followed by tripeptides, etc. A polypeptide is a long and unbranched peptide chain. Hence, peptides fall under the broad chemical classes of biological oligomers and polymers, alongside nucleic acids and polysaccharides, etc. Peptides are distinguished from proteins on the basis of size, as an arbitrary benchmark can be understood to contain 50 or fewer amino acids. Proteins consist of one or more polypeptides arranged in a biologically functional way bound to ligands such as coenzymes and cofactors, or to another protein or other macromolecule, or to complex macromolecular assemblies. While aspects of the lab techniques applied to peptides versus polypeptides and proteins differ, the size boundaries that distinguish peptides from polypeptides and proteins are not absolute: long peptides such as amyloid beta have been referred to as proteins, smaller proteins like insulin have been considered peptides.
Amino acids that have been incorporated into peptides are termed "residues" due to the release of either a hydrogen ion from the amine end or a hydroxyl ion from the carboxyl end, or both, as a water molecule is released during formation of each amide bond. All peptides except cyclic peptides have an N-terminal and C-terminal residue at the end of the peptide. Many kinds of peptides are known, they have been categorized according to their sources and function. According to the Handbook of Biologically Active Peptides, some groups of peptides include plant peptides, bacterial/antibiotic peptides, fungal peptides, invertebrate peptides, amphibian/skin peptides, venom peptides, cancer/anticancer peptides, vaccine peptides, immune/inflammatory peptides, brain peptides, endocrine peptides, ingestive peptides, gastrointestinal peptides, cardiovascular peptides, renal peptides, respiratory peptides, opiate peptides, neurotrophic peptides, blood–brain peptides; some ribosomal peptides are subject to proteolysis.
These function in higher organisms, as hormones and signaling molecules. Some organisms produce peptides as antibiotics, such as microcins. Peptides have posttranslational modifications such as phosphorylation, sulfonation, palmitoylation and disulfide formation. In general, peptides are linear. More exotic manipulations do occur, such as racemization of L-amino acids to D-amino acids in platypus venom. Nonribosomal peptides are assembled by enzymes, not the ribosome. A common non-ribosomal peptide is glutathione, a component of the antioxidant defenses of most aerobic organisms. Other nonribosomal peptides are most common in unicellular organisms and fungi and are synthesized by modular enzyme complexes called nonribosomal peptide synthetases; these complexes are laid out in a similar fashion, they can contain many different modules to perform a diverse set of chemical manipulations on the developing product. These peptides are cyclic and can have complex cyclic structures, although linear nonribosomal peptides are common.
Since the system is related to the machinery for building fatty acids and polyketides, hybrid compounds are found. The presence of oxazoles or thiazoles indicates that the compound was synthesized in this fashion. Peptide fragments refer to fragments of proteins that are used to identify or quantify the source protein; these are the products of enzymatic degradation performed in the laboratory on a controlled sample, but can be forensic or paleontological samples that have been degraded by natural effects. Use of peptides received prominence in molecular biology for several reasons; the first is that peptides allow the creation of peptide antibodies in animals without the need of purifying the protein of interest. This involves synthesizing antigenic peptides of sections of the protein of interest; these will be used to make antibodies in a rabbit or mouse against the protein. Another reason is that techniques such as mass spectrometry enable the identification of proteins based on the peptide masses and sequence that result from their fragmentation.
Peptides have been used in the study of protein structure and function. For example, synthetic peptides can be used as probes to see where protein-peptide interactions occur- see the page on Protein tags. Inhibitory peptides are used in clinical research to examine the effects of peptides on the inhibition of cancer proteins and other diseases. For example, one of the most promising application is through peptides that target LHRH; these particular peptides act as an agonist, meaning that they bind to a cell in a way that regulates LHRH receptors. The process of inhibiting the cell receptors suggests that peptides could be beneficial in treating prostate cancer, but additional investigations and experiments are required before their cancer-fighting attributes can be considered definitive; the peptide families in this section are ribosomal peptides with hormonal activity. All of these peptides are synthesized by cells as longer "propeptides" or "proproteins" and truncated prior to exiting the cell.
They are released into the bloodstream. Magainin family Cecropin famil
In cell biology, the cytoplasm is all of the material within a cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm; the main components of the cytoplasm are cytosol – a gel-like substance, the organelles – the cell's internal sub-structures, various cytoplasmic inclusions. The cytoplasm is about 80% water and colorless; the submicroscopic ground cell substance, or cytoplasmatic matrix which remains after exclusion the cell organelles and particles is groundplasm. It is the hyaloplasm of light microscopy, high complex, polyphasic system in which all of resolvable cytoplasmic elements of are suspended, including the larger organelles such as the ribosomes, the plant plastids, lipid droplets, vacuoles. Most cellular activities take place within the cytoplasm, such as many metabolic pathways including glycolysis, processes such as cell division; the concentrated inner area is called the endoplasm and the outer layer is called the cell cortex or the ectoplasm.
Movement of calcium ions in and out of the cytoplasm is a signaling activity for metabolic processes. In plants, movement of the cytoplasm around vacuoles is known as cytoplasmic streaming; the term was introduced by Rudolf von Kölliker in 1863 as a synonym for protoplasm, but it has come to mean the cell substance and organelles outside the nucleus. There has been certain disagreement on the definition of cytoplasm, as some authors prefer to exclude from it some organelles the vacuoles and sometimes the plastids; the physical properties of the cytoplasm have been contested in recent years. It remains uncertain how the varied components of the cytoplasm interact to allow movement of particles and organelles while maintaining the cell’s structure; the flow of cytoplasmic components plays an important role in many cellular functions which are dependent on the permeability of the cytoplasm. An example of such function is cell signalling, a process, dependent on the manner in which signaling molecules are allowed to diffuse across the cell.
While small signaling molecules like calcium ions are able to diffuse with ease, larger molecules and subcellular structures require aid in moving through the cytoplasm. The irregular dynamics of such particles have given rise to various theories on the nature of the cytoplasm. There has long been evidence, it is thought that the component molecules and structures of the cytoplasm behave at times like a disordered colloidal solution and at other times like an integrated network, forming a solid mass. This theory thus proposes that the cytoplasm exists in distinct fluid and solid phases depending on the level of interaction between cytoplasmic components, which may explain the differential dynamics of different particles observed moving through the cytoplasm, it has been proposed that the cytoplasm behaves like a glass-forming liquid approaching the glass transition. In this theory, the greater the concentration of cytoplasmic components, the less the cytoplasm behaves like a liquid and the more it behaves as a solid glass, freezing larger cytoplasmic components in place.
A cell's ability to vitrify in the absence of metabolic activity, as in dormant periods, may be beneficial as a defence strategy. A solid glass cytoplasm would freeze subcellular structures in place, preventing damage, while allowing the transmission of small proteins and metabolites, helping to kickstart growth upon the cell's revival from dormancy. There has been research examining the motion of cytoplasmic particles independent of the nature of the cytoplasm. In such an alternative approach, the aggregate random forces within the cell caused by motor proteins explain the non-Brownian motion of cytoplasmic constituents; the three major elements of the cytoplasm are the cytosol and inclusions. The cytosol is the portion of the cytoplasm not contained within membrane-bound organelles. Cytosol makes up about 70% of the cell volume and is a complex mixture of cytoskeleton filaments, dissolved molecules, water; the cytosol's filaments include the protein filaments such as actin filaments and microtubules that make up the cytoskeleton, as well as soluble proteins and small structures such as ribosomes and the mysterious vault complexes.
The inner and more fluid portion of the cytoplasm is referred to as endoplasm. Due to this network of fibres and high concentrations of dissolved macromolecules, such as proteins, an effect called macromolecular crowding occurs and the cytosol does not act as an ideal solution; this crowding effect alters. Organelles, are membrane-bound structures inside the cell that have specific functions; some major organelles that are suspended in the cytosol are the mitochondria, the endoplasmic reticulum, the Golgi apparatus, lysosomes, in plant cells, chloroplasts. The inclusions are small particles of insoluble substances suspended in the cytosol. A huge range of inclusions exist in different cell types, range from crystals of calcium oxalate or silicon dioxide in plants, to granules of energy-storage materials such as starch, glycogen, or polyhydroxybutyrate. A widespread example are lipid droplets, which are spherical droplets composed of lipids and proteins that are used in both prokaryotes and eukaryotes as a way of storing lipids such as fatty acids and sterols.
Lipid droplets make up much of the volume of adipocytes, which are specialized lipid-st
Messenger RNA is a large family of RNA molecules that convey genetic information from DNA to the ribosome, where they specify the amino acid sequence of the protein products of gene expression. RNA polymerase transcribes primary transcript mRNA into processed, mature mRNA; this mature mRNA is translated into a polymer of amino acids: a protein, as summarized in the central dogma of molecular biology. As in DNA, mRNA genetic information is in the sequence of nucleotides, which are arranged into codons consisting of three base pairs each; each codon encodes for a specific amino acid, except the stop codons, which terminate protein synthesis. This process of translation of codons into amino acids requires two other types of RNA: Transfer RNA, that mediates recognition of the codon and provides the corresponding amino acid, ribosomal RNA, the central component of the ribosome's protein-manufacturing machinery; the existence of mRNA was first suggested by Jacques Monod and François Jacob, subsequently discovered by Jacob, Sydney Brenner and Matthew Meselson at the California Institute of Technology in 1961.
It should not be confused with mitochondrial DNA. The brief existence of an mRNA molecule begins with transcription, ends in degradation. During its life, an mRNA molecule may be processed and transported prior to translation. Eukaryotic mRNA molecules require extensive processing and transport, while prokaryotic mRNA molecules do not. A molecule of eukaryotic mRNA and the proteins surrounding it are together called a messenger RNP. Transcription is when RNA is made from DNA. During transcription, RNA polymerase makes a copy of a gene from the DNA to mRNA as needed; this process is similar in prokaryotes. One notable difference, however, is that eukaryotic RNA polymerase associates with mRNA-processing enzymes during transcription so that processing can proceed after the start of transcription; the short-lived, unprocessed or processed product is termed precursor mRNA, or pre-mRNA. Processing of mRNA differs among eukaryotes and archea. Non-eukaryotic mRNA is, in essence, mature upon transcription and requires no processing, except in rare cases.
Eukaryotic pre-mRNA, requires extensive processing. A 5' cap is a modified guanine nucleotide, added to the "front" or 5' end of a eukaryotic messenger RNA shortly after the start of transcription; the 5' cap consists of a terminal 7-methylguanosine residue, linked through a 5'-5'-triphosphate bond to the first transcribed nucleotide. Its presence is critical for recognition by the protection from RNases. Cap addition is coupled to transcription, occurs co-transcriptionally, such that each influences the other. Shortly after the start of transcription, the 5' end of the mRNA being synthesized is bound by a cap-synthesizing complex associated with RNA polymerase; this enzymatic complex catalyzes the chemical reactions. Synthesis proceeds as a multi-step biochemical reaction. In some instances, an mRNA will be edited, changing the nucleotide composition of that mRNA. An example in humans is the apolipoprotein B mRNA, edited in some tissues, but not others; the editing creates an early stop codon, upon translation, produces a shorter protein.
Polyadenylation is the covalent linkage of a polyadenylyl moiety to a messenger RNA molecule. In eukaryotic organisms most messenger RNA molecules are polyadenylated at the 3' end, but recent studies have shown that short stretches of uridine are common; the poly tail and the protein bound to it aid in protecting mRNA from degradation by exonucleases. Polyadenylation is important for transcription termination, export of the mRNA from the nucleus, translation. MRNA can be polyadenylated in prokaryotic organisms, where poly tails act to facilitate, rather than impede, exonucleolytic degradation. Polyadenylation occurs during and/or after transcription of DNA into RNA. After transcription has been terminated, the mRNA chain is cleaved through the action of an endonuclease complex associated with RNA polymerase. After the mRNA has been cleaved, around 250 adenosine residues are added to the free 3' end at the cleavage site; this reaction is catalyzed by polyadenylate polymerase. Just as in alternative splicing, there can be more than one polyadenylation variant of an mRNA.
Polyadenylation site mutations occur. The primary RNA transcript of a gene is cleaved at the poly-A addition site, 100–200 A's are added to the 3’ end of the RNA. If this site is altered, an abnormally long and unstable mRNA construct will be formed. Another difference between eukaryotes and prokaryotes is mRNA transport; because eukaryotic transcription and translation is compartmentally separated, eukaryotic mRNAs must be exported from the nucleus to the cytoplasm—a process that may be regulated by different signaling pathways. Mature mRNAs are recognized by their processed modifications and exported through the nuclear pore by binding to the cap-binding proteins CBP20 and CBP80, as well as the transcription/export complex. Multiple mRNA export pathways have been identified in eukaryotes. In spatially complex cells, some mRNAs are transported to particular subcellar destinations. In mature neurons, certain mRNA are transported from the soma to dendrites. One site of mRNA translation is at polyribosomes selectively localized beneath synapses.
The mRNA for Arc/Arg3.1 is induced by synaptic activity and localizes selectively near active synapses based on signals generated by NMDA receptor
Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin -- angiotensin system. Angiotensin stimulates the release of aldosterone from the adrenal cortex to promote sodium retention by the kidneys. An oligopeptide, angiotensin is a dipsogen, it is derived from the precursor molecule angiotensinogen, a serum globulin produced in the liver. Angiotensin was isolated in the late 1930s and subsequently characterized and synthesized by groups at the Cleveland Clinic and Ciba laboratories. Angiotensinogen is an α-2-globulin produced constitutively and released into the circulation by the liver, it is a member of the serpin family, although it is not known to inhibit other enzymes, unlike most serpins. Plasma angiotensinogen levels are increased by plasma corticosteroid, thyroid hormone, angiotensin II levels. Angiotensinogen is known as renin substrate. Human angiotensinogen is 452 amino acids long, but other species have angiotensinogen of varying sizes.
The first 12 amino acids are the most important for activity. Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-... Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu | Val-Ile-... Angiotensin I called proangiotensin, is formed by the action of renin on angiotensinogen. Renin cleaves the peptide bond between the leucine and valine residues on angiotensinogen, creating the decapeptide angiotensin I. Renin is produced in the kidneys in response to renal sympathetic activity, decreased intrarenal blood pressure at the juxtaglomerular cells, or decreased delivery of Na+ and Cl- to the macula densa. If a reduced NaCl concentration in the distal tubule is sensed by the macula densa, renin release by juxtaglomerular cells is increased; this sensing mechanism for macula densa-mediated renin secretion appears to have a specific dependency on chloride ions rather than sodium ions. Studies using isolated preparations of thick ascending limb with glomerulus attached in low NaCl perfusate were unable to inhibit renin secretion when various sodium salts were added but could inhibit renin secretion with the addition of chloride salts.
This, similar findings obtained in vivo, has led some to believe that "the initiating signal for MD control of renin secretion is a change in the rate of NaCl uptake predominantly via a luminal Na,K,2Cl co-transporter whose physiological activity is determined by a change in luminal Cl concentration."Angiotensin I appears to have no direct biological activity and exists as a precursor to angiotensin II. Asp-Arg-Val-Tyr-Ile-His-Pro-PheAngiotensin I is converted to angiotensin II through removal of two C-terminal residues by the enzyme angiotensin-converting enzyme through ACE within the lung. Angiotensin II acts on the CNS to increase vasopressin production, acts on venous and arterial smooth muscle to cause vasoconstriction. Angiotensin II increases aldosterone secretion, therefore, it acts as an endocrine, autocrine/paracrine, intracrine hormone. ACE is a target of ACE inhibitor drugs. Angiotensin II increases blood pressure by stimulating the Gq protein in vascular smooth muscle cells. In addition, angiotensin II acts at the Na+/H+ exchanger in the proximal tubules of the kidney to stimulate Na reabsorption and H+ excretion, coupled to bicarbonate reabsorption.
This results in an increase in blood volume, pH. Hence, ACE inhibitors are major anti-hypertensive drugs. Other cleavage products of ACE, seven or 9 amino acids long, are known; the action of AII itself is targeted by angiotensin II receptor antagonists, which directly block angiotensin II AT1 receptors. Angiotensin II is degraded to angiotensin III by angiotensinases located in red blood cells and the vascular beds of most tissues, it has a half-life in circulation of around 30 seconds, whereas, in tissue, it may be as long as 15–30 minutes. Angiotensin II results in increased inotropy, catecholamine release, catecholamine sensitivity, aldosterone levels, vasopressin levels, cardiac remodeling and vasoconstriction through AT1 receptors on peripheral vessels; this is why ACE inhibitors and ARBs help to prevent remodeling that occurs secondary to angiotensin II and are beneficial in CHF. Asp | Arg-Val-Tyr-Ile-His-Pro-PheAngiotensin III has 40% of the pressor activity of angiotensin II, but 100% of the aldosterone-producing activity.
Increases mean arterial pressure. Arg | Val-Tyr-Ile-His-Pro-PheAngiotensin IV is a hexapeptide that, like angiotensin III, has some lesser activity. Angiotensin IV has a wide range of activities in the central nervous system; the exact identity of AT4 receptors has not been established. There is evidence. There is evidence that angiotensin IV interacts with the HGF system through the c-Met receptor. Synthetic small molecule analogues of angiotensin IV with the ability to penetrate through blood brain barrier have been developed. See Renin–angiotensin system#EffectsAngiotensins II, III and IV have a number of effects throughout the body: Angiotensins "modulate fat mass expansion through upregulation of adipose tissue lipogenesis... and downregulati
The endoplasmic reticulum is a type of organelle found in eukaryotic cells that forms an interconnected network of flattened, membrane-enclosed sacs or tube-like structures known as cisternae. The membranes of the ER are continuous with the outer nuclear membrane; the endoplasmic reticulum occurs in most types of eukaryotic cells, but is absent from red blood cells and spermatozoa. There are two types of ER: smooth endoplasmic reticulum; the outer face of the rough endoplasmic reticulum is studded with ribosomes that are the sites of protein synthesis. The rough endoplasmic reticulum is prominent in cells such as hepatocytes; the smooth endoplasmic reticulum lacks ribosomes and functions in lipid synthesis but not metabolism, the production of steroid hormones, detoxification. The smooth ER is abundant in mammalian liver and gonad cells; the ER was observed with light microscope by Garnier in 1897, who coined the term "ergastoplasm". With electron microscopy, the lacy membranes of the endoplasmic reticulum were first seen in 1945 by Keith R. Porter, Albert Claude, Ernest F. Fullam.
The word "reticulum", which means "network", was applied by Porter in 1953 to describe this fabric of membranes. The general structure of the endoplasmic reticulum is a network of membranes called cisternae; these sac-like structures are held together by the cytoskeleton. The phospholipid membrane encloses the cisternal space, continuous with the perinuclear space but separate from the cytosol; the functions of the endoplasmic reticulum can be summarized as the synthesis and export of proteins and membrane lipids, but varies between ER and cell type and cell function. The quantity of both rough and smooth endoplasmic reticulum in a cell can interchange from one type to the other, depending on the changing metabolic activities of the cell. Transformation can include embedding of new proteins in membrane as well as structural changes. Changes in protein content may occur without noticeable structural changes; the surface of the rough endoplasmic reticulum is studded with protein-manufacturing ribosomes giving it a "rough" appearance.
The binding site of the ribosome on the rough endoplasmic reticulum is the translocon. However, the ribosomes are not a stable part of this organelle's structure as they are being bound and released from the membrane. A ribosome only binds to the RER; this special complex forms when a free ribosome begins translating the mRNA of a protein destined for the secretory pathway. The first 5–30 amino acids polymerized encode a signal peptide, a molecular message, recognized and bound by a signal recognition particle. Translation pauses and the ribosome complex binds to the RER translocon where translation continues with the nascent protein forming into the RER lumen and/or membrane; the protein is processed in the ER lumen by an enzyme. Ribosomes at this point may be released back into the cytosol; the membrane of the rough endoplasmic reticulum forms large double membrane sheets that are located near, continuous with, the outer layer of the nuclear envelope. The double membrane sheets are stacked and connected through several right or left-handed helical ramps, the so-called Terasaki ramps, giving rise to a structure resembling a multi-storey car park.
Although there is no continuous membrane between the endoplasmic reticulum and the Golgi apparatus, membrane-bound transport vesicles shuttle proteins between these two compartments. Vesicles are surrounded by coating proteins called COPI and COPII. COPII targets vesicles to the Golgi apparatus and COPI marks them to be brought back to the rough endoplasmic reticulum; the rough endoplasmic reticulum works in concert with the Golgi complex to target new proteins to their proper destinations. A second method of transport out of the endoplasmic reticulum involves areas called membrane contact sites, where the membranes of the endoplasmic reticulum and other organelles are held together, allowing the transfer of lipids and other small molecules; the rough endoplasmic reticulum is key in multiple functions: Manufacture of lysosomal enzymes with a mannose-6-phosphate marker added in the cis-Golgi network. Manufacture of secreted proteins, either secreted constitutively with no tag or secreted in a regulatory manner involving clathrin and paired basic amino acids in the signal peptide.
Integral membrane proteins that stay embedded in the membrane as vesicles exit and bind to new membranes. Rab proteins are key in targeting the membrane. Initial glycosylation as assembly continues; this is N-linked. N-linked glycosylation: If the protein is properly folded, Oligosaccharyltransferase recognizes the AA sequence NXS or NXT and adds a 14-sugar backbone to the side-chain nitrogen of Asn. In most cells the smooth endoplasmic reticulum is scarce. Instead there are areas where the ER is smooth and rough, this area is called the transitional ER; the transitional ER gets its name. These are areas where the transport vesicles that contain lipids and proteins made in the ER, detach from the ER and start moving to the Golgi apparatus. Specialized cells can have a lot of smooth endoplasmic reticulum and in these cells the smooth ER has many functions
Leptin is a hormone predominantly made by adipose cells that helps to regulate energy balance by inhibiting hunger. This hormone acts on receptors in the arcuate nucleus of the hypothalamus. In obesity, a decreased sensitivity to leptin occurs, resulting in an inability to detect satiety despite high energy stores and high levels of leptin. Although regulation of fat stores is deemed to be the primary function of leptin, it plays a role in other physiological processes, as evidenced by its many sites of synthesis other than fat cells, the many cell types beside hypothalamic cells that have leptin receptors. Many of these additional functions are yet to be defined. Predominantly, the "energy expenditure hormone" leptin is made by adipose cells, thus it is labeled fat cell-specific. In the context of its effects, it is important to recognize that the short describing words direct and primary are not used interchangeably. In regard to the hormone leptin, central vs peripheral refers to the hypothalamic portion of the brain vs non-hypothalamic location of action of leptin.
Location of action Leptin acts directly on leptin receptors in the cell membrane of different types of cells in the human body in particular, in vertebrates in general. The leptin receptor is found on a wide range of cell types, it is a single-transmembrane-domain type I cytokine a special class of cytokine receptors. Further, leptin interacts with other hormones and energy regulators, indirectly mediating the effects of: insulin, insulin-like growth factor, growth hormone, glucocorticoids and metabolites. Mode of action The central location of action of the fat cell-specific hormone leptin is the hypothalamus, a part of the brain, a part of the central nervous system. Non-hypothalamic targets of leptin are referred to as peripheral targets. There is a different relative importance of central and peripheral leptin interactions under different physiologic states, variations between species. Function The primary function of the hormone leptin is the regulation of adipose tissue mass through central hypothalamus mediated effects on hunger, food energy use, physical exercise and energy balance.
Outside the brain, in the periphery of the body, leptin's secondary functions are: modulation of energy expenditure, modulation between fetal and maternal metabolism, that of a permissive factor in puberty, activator of immune cells, activator of beta islet cells, growth factor. In vertebrates, the nervous system consists of two main parts, the central nervous system and the peripheral nervous system; the primary effect of leptins is in the hypothalamus, a part of the central nervous system. Leptin receptors are expressed not only in the hypothalamus but in other brain regions in the hippocampus, thus some leptin receptors in the brain are classified as some as peripheral. As scientifically known so far, the general effects of leptin in the central nervous system are: Deficiency of leptin has been shown to alter brain proteins and neuronal functions of obese mice which can be restored by leptin injection. In humans, low circulating plasma leptin has been associated with cognitive changes associated with anorexia and Alzheimer’s Disease.
Studies in transgenic mouse models of Alzheimer's disease have shown that chronic administration of leptin can ameliorate brain pathology and improve cognitive performance, by reducing b-amyloid and hyperphosphorylated Tau, two hallmarks of Alzheimer's pathology. Leptin is thought to enter the brain at the choroid plexus, where the intense expression of a form of leptin receptor molecule could act as a transport mechanism. Increased levels of melatonin causes a downregulation of leptin, melatonin appears to increase leptin levels in the presence of insulin, therefore causing a decrease in appetite during sleeping. Partial sleep deprivation has been associated with decreased leptin levels. Mice with type 1 diabetes treated with leptin or leptin plus insulin, compared to insulin alone had better metabolic profiles: blood sugar did not fluctuate so much. Leptin acts on receptors in the lateral hypothalamus to inhibit hunger and the medial hypothalamus to stimulate satiety. In the lateral hypothalamus, leptin inhibits hunger by counteracting the effects of neuropeptide Y, a potent hunger promoter secreted by cells in the gut and in the hypothalamus counteracting the effects of anandamide, another potent hunger promoter that binds to the same receptors as THC In the medial hypothalamus, leptin stimulates satiety by promoting the synthesis of α-MSH, a hunger suppressantThus, a lesion in the lateral hypothalamus causes anorexia and a lesion in the medial hypothalamus causes excessive hunger.
This appetite inhibition is long-term, in contrast to the rapid inhibition of hunger by cholecystokinin and the slower suppression of hunger between meals mediated by PYY3-36. The absence of leptin leads to resulting obesity. Fasting or following a very-low-calorie diet lowers leptin levels. Leptin levels change more; the dynamics of leptin due to an acute change in energy balance may be related to appetite and to food intake rather than fat stores. It controls food intake and energy expenditure by acting