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To maintainhomeostasis in humans, a wide array of extracellular factors is involved to harmonise physiological activities among organs and cell types.

Thesesignalling molecules in the form of hormones, peptides, neurotransmitters,proteins, ions, and lipids act via specific receptors to elicit cellularresponses. Among all the receptor families, more than 700 G protein-coupledreceptors (GPCRs) form the largest and the most diverse receptor group thatparticipate in virtually all aspects of human physiology. Their physiologicalrelevance makes them one of the most popular drug targets, remarkably abouthalf of all known drugs act through GPRCs or the signaling pathways of GPCRs(Alberts et al., 2002). The identification of the molecular mechanismsunderlying GPCR signaling has progressed rapidly in recent years (see Eglen,2005; Katritch et al.

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, 2013; Wacker et al., 2017), and theunderstanding of GPCRs in the field of endocrinology is further contributed . Theendocrine diseases related to GPCR mutations clearly reflect their importancein regulating the endocrine systemWYH1 by the naturallyoccurring mutations found in patientswith endocrine diseases  (Vassart and Costagliola, 2011). The classical endocrine systemrefers to glands that release hormones into the bloodstream and reaching itstarget in a distant part of the body.

However, over the past twenty years, ithas become clear that the regulations of hormone secretion, as well as thephysiological responses within the target organs are mediated by more fundamentalcommunications within the local regionWYH2 . Those communications are known asparacrine, autocrine, juxtacrine and intracrine interactions (Lodish, 2016). In this review, we will focus on ourcurrent, yet evolving, understanding of the autocrine and paracrine signals regulatedby GPCRs in various physiological systems. Nevertheless, with more knowledgebeing established regarding cell-cell interaction mechanisms, it has become obviousthat signals mediated by GPCRs are regulated by a myriad of complexdeterminants, and could lead to the crosstalk between different signalingpathways, culminating in an adjusted regulatory effect on target cells.

Consequently, thisreview will not only focus on well-established paradigms of GPCRs inautocrine/paracrine regulations, but will also discuss the role of GPCRs beingused to mediate the physiological responses of endocrine organs in the contextof signaling pathways, which may provide a broader insight for future pharmaceutical development.   GPCRs and the hierarchy of endocrine, autocrine and paracrine signalling Although the discovery ofautocrine and paracrine interactions was initially overshadowed by thecharacterization of endocrine glands, the concept of cells being able to secreteregulatory elements has been appreciated more than 200 years ago (see Thompson & Bradshaw, 2003). Now it has become clear that the endocrine glands areregulated by a plethora of internal and external signals via blood circulation,and these input signals trigger the release of localized autocrine/paracrine messengers.The pool of autocrine/paracrine factors contribute to the communications and intricatefeedbacks between different cells within the endocrine gland, resulting in acoordinated hormonal outputand the corresponding physiological outcome.

Noticeably, the same chemical moleculecan be used in multiple contexts of endocrine, paracrine or autocrinesignaling, or even in synaptic signaling. But the function of signalingmolecules can be considered in a hierarchical way for majorityof the endocrine organs (Figure 1):(1) As a circulatory input that initiate the localized following autocrine/paracrineinteractionsWYH3 LHT4 ; (2) As an autocrine/paracrine messenger that mediate the feedbacknetwork among different cells within the endocrine gland; (3) As a hormonaloutput secreted by endocrine cells, which enter the circulation and furtherserve as a circulatory input for other organs.  Among thesesignaling processes, the prevalence of GPCRs make them ineluctable targets forfunctional studies and endocrine pharmaceutics. Hence, weare going to illustrate the roles of GPCRs in mediating endocrine signals inthe following aspects: (1)From the circulatory input to the endocrine gland, GPCRs mediating mediatethe transition from endocrine and other circulatory signals intoautocrine/paracrine signals; (2) Within the endocrine gland, GPCRs respondingrespond to autocrine/paracrine factorsand contributing contribute to theautocrine/paracrine regulatory network that modulate thehormonal output of the organ;; (3) Withina single cell inside the gland, tTheexpression of different GPCRs on different cells in the endocrine glands, helpsto adjust different signaling effects of the messengers, thusenabling an integrated output from the hormonal output fromthe organcell. The examples being discussed inthis review are mainly related to energy homeostasis, as it is a vitalprerequisite for survival by optimizingnutrient utilization. Yetthe concept of GPCRs in the mediation of autocrine/paracrine responses can beapplied to many other endocrine organs that are not mentioned.   GPCRs in pancreatic islet Pancreatic islet is a peripheral endocrinegland that plays a key role in maintaining blood glucose level and energyhomeostasis.

To adjust the energy fluctuation caused by food intake, circadianrhythm and physical activities, the islet is sensitive to internal signals whichare governed by the hypothalamus, as well as other circulatory nutrients andhormones that are influenced by the external environment. Examples of GPCRsinvolved in these processes are listed in Table 1.   For sensing circulatory inputs There are numerous GPCRs that recognizecirculatory nutrients and related hormones.

One of the best known incretinhormones is glucagon-like peptide 1 (GLP1), which is mainly produced andsecreted by intestinal L-cells upon food consumption and then circulates to the islet.GLP1 receptor (GLP1R) couples to the Gs signaling pathway to controlthe secretion of insulin, glucagon, and somatostatin that facilitate glucosedisposal. The activation of GLP1R on ?-cells induces arobust up-regulation of insulin-like growth factor 1 (IGF1) receptorexpression, and triggers the IGF2/IGF1 receptor autocrine loop associated withan increase of Akt phosphorylation, which the Akt pathwayis the basis for the anti-apoptotic effect WYH5 (Cornu et al., 2010). GLP1R expressed on ?- and ?-cells can also direct theparacrine regulations by activating the secretion of insulin and somatostatinthat inhibit glucagon secretion by ?-cells. G astricinhibitory polypeptide (GIP)WYH6 , anotherincretin hormone which signals via GIPR and the Gs signalingpathway, can also mediate similar routes but is less understood (seeAhrén2009). Untilrecently it was found that GIP can induce production of IL6 by ? cells, , while another paracrine role of GIPR has been suggestedWYH7 . Activation of GIPR on ?-cells could lead to the productionof IL6, which in turn stimulates the production of GLP1 andinsulin secretion by ?-cell (Timper et al.

, 2016). Besides,free fatty acids (FFAs) provide an important energy source as nutrients, and they act as ligands ofseveral GPCRs including GPR40, GPR41, GPR43, GPR84, GPR119 and GPR120WYH8  (Ichimuraet al., 2009).

 Among these GPCRs, GPR40 (also known as FFAR1) isexpressed in human islets at levels comparable to those of GLP1R. It has beendemonstrated that palmitate can enhancethe secretion of glucagon and insulin via GPR40 on ?- and ?-cells at fastingglucose level (Kristinsson et al.,2017), and this positive regulation is primarily transducedthrough the Gq/11 signaling pathway (Briscoe et al., 2003). AnotherFFA receptor, GRP119 is expressed predominantly in?-cells.

Binding of long chain FFAs to the GPR119 receptor causes an increasein intracellular cAMP levels via Gs couplingto adenylate cyclase (AC). In vitro studieshave indicated a role for GPR119 in promoting glucose-stimulated insulinsecretion (GSIS) (Overton et al., 2008).  Apart fromthe molecules that are determined by food uptake, the pancreatic islet is alsoinfluenced by signals from the central nervous system (CNS). Multiple studies have demonstrated the metabolic rolesof circadian clocksin key metabolic tissues, including liver, pancreas, white adipose, and skeletal muscle (see Huang et al.

, 2011). In mammals, the suprachiasmaticnuclei (SCNWYH9 ) expressa robust circadian rhythm of electrophysiological activity, which is known toplay a key role in circadian rhythm generation (see Gillette and Mitchell 2002; Hannibal 2002). As anoscillator, the SCN controls the melatonin secretion rhythm by the pinealgland. The expression of melatoninreceptors MT1 andMT2 inthe human islets has been evidenced by molecular and immunocytochemicalinvestigation (Peschke etal.

, 2007) and the influence of melatonin onpancreatic ?-cells is connected with a Gi signaling pathways, whichinhibits AC activity and hence lower the cAMP level and the insulin secretion.The MT2 receptor is also found to inhibit the insulin secretion by suppressing the guanylate cyclase/cyclic guanosinemonophosphate (GC/cGMP) pathway (Stumpf et al., 2008). Besides, the inhibitory effect of melatonin on somatostatinsecretion has been demonstrated in a human pancreatic ?-cell WYH10 line recently (Zibolka et al., 2015). Classical neurotransmitters such as noradrenaline and adrenalinecan also regulate pancreatic hormone secretion. The ?2-adrenoceptors (?2A, ?2B and ?2C) and?-adrenoceptors (?1, ?2 and?3) are widely expressed in the body (Alexander et al.

, 2017), with their physiological functions extensively studied in animal models. The ?2A-adrenoceptoron ?-cell is important in Gi/o-mediated inhibition ofinsulin secretion. Although it is less studiedin humans, the ?2A-adrenoceptoragonist can prevent excess insulin release (Fagerholm et al., 2011), andvariants of ?2A-adrenoceptorare associated with type II diabetes (Talmud et al., 2011).

Whereas ?-adrenoceptors that arecoupled to Gs work in the opposite directionand enhance insulin secretion (Porte, 1967). It has also beennoticed that ?1-/?2-adrenoceptors (?1-/?2ARs)can increase somatostatin content and transcription in mice via ?-arrestin 1 inaddition to the Gs pathway (Wang et al., 2014).   Formediating autocrine/paracrine regulations ForinstanceWYH11 , 293islet GPCRs and 271 different endogenous ligands have been identified in human,of which at least 131 ligands are present in islet cells (Amisten et al.,2013).

However, the majority of islet GPCRs have unknown effects on pancreatichormone secretion. Readers may refer to other reviews for the full list ofislet GPCRs discovered in humans andtheir comparative analysis with mouse islet GPCRs (Amisten et al., 2013;Amisten et al., 2017). Interestingly, among all those endogenous ligands, 119of them activate more than one receptor in the islet; the redundancy insignaling suggests that a ligand is able to trigger a variety of GPCRs that arelikely present on multiple cell types, thereby diversifying the signaling eventand inferring a robust paracrine regulatory mechanism.    Uponreceiving various input signals, islet cells in turn secreteautocrine/paracrine molecules that influence the activity of neighbouringcells.

The paracrine interactions between ?-, ?- and ?-cells have been proposedfor a long time, with the somatostatin-secreting ?-cells provide essentialnegative feedback to both insulin and glucagon release, and theglucagon-secreting ?-cells positively regulating insulin and somatostatinsecretion (Taborsky et al., 1978; Rorsman and Braun, 2013; Caicedo, 2013; Gylfe and Gilon, 2014). Thereare five human somatostatin receptor subtypes (SSTR1-5) with only SSTR1, SSTR2, and SSTR5showing predominanthigh WYH12 expressionlevel in islets. SSTR1 and SSTR2 areselectively expressed on ?-cells and ?-cells, respectively. SSTR5is well expressed on both ?-and ?-cells, and moderately well expressed on all ?-cells (Kumar et al., 1999). All SSTRs are Gi/o-coupled,SSTR2 and SSTR5 can also signal through Gq/11 G-protein.As demonstrated in the mice model, the inhibitory effect on insulin andglucagon secretion is mediated by SSTR5 (Strowski et al.

, 2003) andSSTR2, respectively (Strowski et al., 2000). While ?-cells act as aparacrine repressor, ?-cells work as a positively regulator.

Acetylcholineproduced by ?-cells is able to stimulates the insulin secretion by ?-cellsvia the muscarinic receptors M3 and M5, andthe somatostatin secretion by ?-cells throughM1 (Molinaet al., 2014). M1, M3and M5 are all coupled to Gq/11signaling pathway (Bräuner-Osborne & Brann, 1996).  CB1is densely located in ?-cells. In vitro experiments revealed that the activation of CB1receptor can enhance insulin and glucagon secretion, which suggests that CB1 canmediate both paracrine and autocrine communication (Bermudez-Silva etal., 2008).

Apartfrom the paracrine feedback system, the glucagon positive autocrine feedbackloop has been revealed in ?-cells. Glucagon secreted by the ?-cells canupregulate the expression of its own gene,.Which the which the processis signals WYH13 throughmediatedby the glucagon receptor and the Gs-mediated signaltransduction (Leibiger et al.

, 2012). Since the release ofglucagon is stimulated by lack of glucose, t. WYH14 This kind of positive feedback mayhelp to optimize the hormonal output response under less favourable energeticconditions.    GPCRs in brain for regulatingenergy homeostasisLHT15  The brain influences theendocrine system in response to environmental changes. The effect ofcirculatory hormones, in turn, can regulate the brain chemistry and structure.

Similar to peripheral endocrine glands, the stimulation of brain by thecirculatory inputs can trigger a sophisticated autocrine/paracrine feedbacknetwork, which generates integrated output signals that regulate the body inreturn. But different from the peripheral glands, the autocrine/paracrineregulation in brain usually involves the synaptic signal transduction, whichenhance the specificity of message delivery, and the physical distance betweenmessage sender and recipient can be longer.   From circulatory inputsto neuroendocrine signals In the case of energyhomeostasis, it is important for the brain to sense the level of metabolicsubstances so that regulate the energy usage. Inside the CNS, the hypothalamusis considered as an essential place where the nervous system and the endocrinesystem meet. Metabolic signals such as glucose, insulin, cholecystokinin (CCK),pancreatic polypeptides (PP and PYY) and ghrelin have all been found tomodulate the hypothalamic arcuate nucleus (ARC), altering the food intake andmetabolism (see Abizaid & Horvath, 2008). Examples of GPCRs involved inreceiving metabolic inputs are listed in Table 2. Among these signals, ghrelinhas received a great research interest as it can upregulate food intake whilethe majority acts in opposite way (see Abizaid & Horvath, 2008). Thecirculatory ghrelin is mainly produced by the gastric X/A-like cells of oxynticstomach mucosa under hunger situation (Date et al.

, 2000). In CNS, ghrelinreceptor type 1a (GHSR1a) is highly expressed in the ARC and ventromendial nucleus(VMN) of the hypothalamus (Ferrini et al., 2009). By activating thephospholipase C (PLC) via Gq/11-protein, GHSR1a triggers the release ofNPY that exerts paracrine effects (which will be discussed later). Theheteromerization of GHSR1a with other GPCRs further broadens its downstreamresponses. Various studies suggest that GHSR1a specificallyforms dimers with the SST5R (Schellekens et al.

,2013), D1R (Jiang et al., 2006; Schellekens et al., 2012) and D2R(Kern et al., 2012), MC3R (Schellekens et al.,2012), and 5-HT2cR (Schellekens et al., 2012). Involvement of heterodimersof the GHS-R1a with D1R or D2R has been demonstrated in dopaminergic mesolimbic circuitsthat are responsible for reward signaling of food (Pradhan et al.

,2013). In contrast, many circulatory signals tends down-regulate theenergy intake. PYY are stimulated during meal intake by the presence ofnutrients in the small intestine, especially fat. Y2receptor (Y2R), which is coupled to Gi/o-and Gq/11 proteins, is critical in mediating the effects of PYY3–36on reducing adiposity and feeding. The expression of Y2Rcan be found throughout the CNS, within the nodose ganglion and on vagalafferents, thus the feeding effects of PYY3-36 is possiblymediated through central, vagal activation or combinations of both (see Karraet al.

, 2009). The pattern of c-fos neuronal activation following peripheraladministration of PYY3–36 further suggests the involvement of Y2Rsin ARC (Karra et al., 2009).   Paracrine andautocrine regulations in hypothalamus for energy homeostasis Within the hypothalamus, ghrelin bound mostlyon presynaptic terminals of NPY neurons and stimulates the activity of arcuateNPY as evidenced by electrophysiological recordings (Cowley et al., 2003).

Further studieshave demonstrated the inhibitory effect of NPY on the release of POMC, thyroidhormone (THS) and corticotropin releasing hormones (CRH), and stimulate thesecretion of hypocretin/orexin and melanin-concentrating hormone (MCH) from thelateral hypothalamus (LH), which regulate metabolism throughmultiple output pathways that eventually enhance appetite (see Abizaid and Horvath, 2008).  In contrast, MCH receptor 1 (MCH1R) knockout mice are leaner,eat less and have increased metabolism than their wild type littermates (Marshet al., 2002)  ARC NPY expression is regulatedin an autocrine manner via presynaptic NPY2 receptors presentin NPY neurons to decrease NPY expression (Acuna-Goycolea & van den Pol,2005).  POMC modulates energy homeostasis principallythrough central melanocortin systemwhich exerts a tonic inhibitory control on food intake and energy storage in particular the ventromedial hypothalamicnucleus (VMH), was clearly associated with increased food intake, morbidobesity and insulin resistance, while damage to more lateral hypothalamicstructureswas associated with anorexia and adipsia (Anand & Brobeck, 1951)  it is widely accepted that the control of foodintake occurs through activation of specific hypothalamic nuclei and thepromotion of neuropeptide Y (NPY) and Agouti related protein (AgRP) expression4, 5, 103, 142, 145, 148, 157,the distribution of GHSR in central nervous system (CNS), and the modulation ofneurotransmission in extra-hypothalamic areas suggest broader effects thanoriginally predicted. This is supported by the fact that, in addition to NPY,the ARC also contains a second set of neurons that produce ?-melanocytestimulating hormone (?-MSH), an anorectic peptide formed fromthe cleavage ofthe proopiomelanocortin (POMC) protein 34. This protein acts on melanocortinreceptors types 3 and 4 (MC3/4, respectively) present in various hypothalamicnuclei to reduce food intake and energy expenditure in a manner similar toleptin. In addition, NPY neuronsproduce a secondorexigenic peptide, theagoutirelatedpeptide (Agrp), an endogenous antagonist to the MC3/4 receptor 38.Thispeptide, likeNPY, increases food intake dramatically, but the increase infoodintakeproducedby this peptide is longlasting, andeffect that is stillnotwell understood 39.

Similarly, POMC cells also synthesize a secondanorexic peptide, the cocaine and amphetamine related transcript (CART). Therelative contribution of CART versus ?-MSH in the regulation of food intake andenergy expenditure remains unexplained. What is known is that both NPY/Agrp andPOMC/CART neuronswithin the ARC appear to primarily modulate food intake viatheir outputtargets because the ARC contains the largestconcentration of cells thatproduce NPY and have the densest concentration ofleptin sensitive neurons inthe brain, it is generally acceptedthat thisregionis key to the regulation of energy balance (Fig.1).  Finally,NPY/Agrp neurons in the ARC appear tosynapse onto neighboring POMC/CARTcells to inhibit themusing GABA as aneurotransmitter   The ghrelin receptor (GHSR),which is mainly expressedon NPY/AGRP producing neurons in the ARC of the hypothalamusb16 ,  CCKB primarilyCNS, lesser amounts in the gastrointestinal tract, CCKA primarily GI, less inCNS  WYH1Re-write. WYH2Meaning? WYH3Thisis confusing. Seems to be similar to (2) LHT4Usefigure to illustrate WYH5Effectof GLP1 or IGF? WYH6Define. WYH7Reference? WYH8Referenceor review citation.

 WYH9Define. WYH10Acell or a cell line? WYH11Nota good way to start a paragraph. WYH12Thismeans they are not found elsewhere. Do you mean abundant? WYH13Incorrectgrammar. WYH14Incompletesentence. LHT15 b16Statementslike this will need a citation.

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