Urocortin II

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Urocortin II
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Urocortin 2 (Ucn2) is an endogenous peptide in the corticotrophin-releasing factor (CRF) family. [1]

Contents

Urocortin II is a 38-amino acid peptide that is a member of the CRF family of peptides. Unlike Urocortin I, Urocortin II is highly selective for the CRF2 receptor and does not show affinity for the CRF binding protein.

Function

Urocortin (UCN) II, also known as stresscopin-related peptide, is a 38 amino acid member of the mammalian corticotropin-releasing hormone (CRH) peptide family, which also includes CRH, UCN I, and UCN III. [1] [2] CRH mainly binds to type 1 CRH receptors (CRH1), while UCN II and III bind primarily to type 2 CRH receptors, and UCN I binds to both (CRH2). [1] [2] Each of these hormones has distinctive distribution patterns in the central nervous system and the periphery, suggesting each peptide may have distinct behavioral and physiological effects, although all have been associated with anxiety. [2] [3] [4] [5] In general, agonism of CRH1 receptors is posited to be anxiogenic and agonism of CRH2 receptors is posited to be anxiolytic. [6]

Urocortin II has been shown to have anorexigenic effects and hypotensive effects similar to Urocortin, but does not induce secretion of ACTH.

Receptor

The activation of cAMP/PKA by Ucn2 gives similar effects to the β-adrenergic pathway. Ucn2 increases left ventricular function independent of the β-adrenergic receptor but dependent on the binding of Ucn2 to CFR2. [6] [7] [8] [9] Ucn2 is an agonist for the G-protein coupled CRF1 and CRF2 receptors. It is highly selective for CRF2 which is predominantly found in the myocardium, blood vessels and peripheral tissues. This association provides reason for its strong cardiovascular effects. When Ucn2 binds CRF2 it activates adenyl-cyclase to increase cAMP which activates PKA and results in the noted changes to cardiovascular function. [1]

The ability of Ucn2 to produce PKA and alter calcium flux has led to the hypothesis that administration of Ucn2 may increase the risk of arrhythmias. [7] [8] [9]

Clinical significance

Immunohistochemistry analysis of human myocytes has shown greater immunoreactivity of Ucn2 in myocytes of the failing heart compared to those of the healthy heart. This is a result of an innate mechanism in which Ucn2 acts to improve function of the failing heart. [2] The pathophysiology of heart failure is often a consequence of improper calcium handling and relaxation resulting in a lower cardiac output, decreased blood flow and overall decreased heart function. [3] Infusion of Ucn2 in healthy humans has shown a dose dependent increase in cardiac output, heart rate and left ventricle ejection fraction and a decrease in systemic vascular resistance. [4] Ucn2 has been studied as potential treatment for individuals with heart failure.

Animal studies

Infusion of Ucn2 into rat hearts resulted in an immediate and significant improvement in left ventricle function, increased coronary flow, significantly altered intracellular calcium handling and increased SR calcium. [5] These relaxation effects can be explained by the increased calcium clearance into the SR would assist in relaxation of the cell. Increased calcium in the SR by Ucn2 is a result of Ucn2 mediated production of cAMP and phosphokinase A (PKA). [7] [8] [9] Ucn2 increases cAMP levels in myocytes and nonmyocytes. [2] The production of PKA results in the phosphorylation of phospholamban and inhibition of its block on the sarcoendoplasmic reticulum calcium ATPase (SERCA). [7] [8] [9] In rat coronary vessels, PKA mediates inhibition of calcium-independent phospholipase A and calcium influx which results in relaxation of the vasculature. [10] This suggests Ucn2 may be beneficial in improving blood but these findings have less biological applicability to human medicine as they were completed on rats. In 2011 a similar relationship was found in human heart. [9] Ucn2 produced a dose dependent relaxation of coronary. This correlation was a result of the cAMP/ PKA pathway and independent of endothelial function. Ucn2 may be a beneficial drug in damaged hearts where the endothelium is not intact. [1]

Related Research Articles

<span class="mw-page-title-main">Corticotropin-releasing hormone</span> Mammalian protein found in Homo sapiens

Corticotropin-releasing hormone (CRH) is a peptide hormone involved in stress responses. It is a releasing hormone that belongs to corticotropin-releasing factor family. In humans, it is encoded by the CRH gene. Its main function is the stimulation of the pituitary synthesis of adrenocorticotropic hormone (ACTH), as part of the hypothalamic–pituitary–adrenal axis.

<span class="mw-page-title-main">Adrenergic receptor</span> Class of G protein-coupled receptors

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Corticotropin-releasing factor family, CRF family is a family of related neuropeptides in vertebrates. This family includes corticotropin-releasing hormone, urotensin-I, urocortin, and sauvagine. The family can be grouped into 2 separate paralogous lineages, with urotensin-I, urocortin and sauvagine in one group and CRH forming the other group. Urocortin and sauvagine appear to represent orthologues of fish urotensin-I in mammals and amphibians, respectively. The peptides have a variety of physiological effects on stress and anxiety, vasoregulation, thermoregulation, growth and metabolism, metamorphosis and reproduction in various species, and are all released as prohormones.

<span class="mw-page-title-main">Sarcoplasmic reticulum</span> Menbrane-bound structure in muscle cells for storing calcium

The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other cells. The main function of the SR is to store calcium ions (Ca2+). Calcium ion levels are kept relatively constant, with the concentration of calcium ions within a cell being 10,000 times smaller than the concentration of calcium ions outside the cell. This means that small increases in calcium ions within the cell are easily detected and can bring about important cellular changes (the calcium is said to be a second messenger. Calcium is used to make calcium carbonate (found in chalk) and calcium phosphate, two compounds that the body uses to make teeth and bones. This means that too much calcium within the cells can lead to hardening (calcification) of certain intracellular structures, including the mitochondria, leading to cell death. Therefore, it is vital that calcium ion levels are controlled tightly, and can be released into the cell when necessary and then removed from the cell.

<span class="mw-page-title-main">Atrial natriuretic peptide</span> Cardiac hormone which increases renal sodium excretion

Atrial natriuretic peptide (ANP) or atrial natriuretic factor (ANF) is a natriuretic peptide hormone secreted from the cardiac atria that in humans is encoded by the NPPA gene. Natriuretic peptides are a family of hormone/paracrine factors that are structurally related. The main function of ANP is causing a reduction in expanded extracellular fluid (ECF) volume by increasing renal sodium excretion. ANP is synthesized and secreted by cardiac muscle cells in the walls of the atria in the heart. These cells contain volume receptors which respond to increased stretching of the atrial wall due to increased atrial blood volume.

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Corticotropes are basophilic cells in the anterior pituitary that produce pro-opiomelanocortin (POMC) which undergoes cleavage to adrenocorticotropin (ACTH), β-lipotropin (β-LPH), and melanocyte-stimulating hormone (MSH). These cells are stimulated by corticotropin releasing hormone (CRH) and make up 15–20% of the cells in the anterior pituitary. The release of ACTH from the corticotropic cells is controlled by CRH, which is formed in the cell bodies of parvocellular neurosecretory cells within the paraventricular nucleus of the hypothalamus and passes to the corticotropes in the anterior pituitary via the hypophyseal portal system. Adrenocorticotropin hormone stimulates the adrenal cortex to release glucocorticoids and plays an important role in the stress response.

<span class="mw-page-title-main">Milrinone</span> Chemical compound

Milrinone, sold under the brand name Primacor, is a pulmonary vasodilator used in patients who have heart failure. It is a phosphodiesterase 3 inhibitor that works to increase the heart's contractility and decrease pulmonary vascular resistance. Milrinone also works to vasodilate which helps alleviate increased pressures (afterload) on the heart, thus improving its pumping action. While it has been used in people with heart failure for many years, studies suggest that milrinone may exhibit some negative side effects that have caused some debate about its use clinically.

<span class="mw-page-title-main">Urocortin</span>

Urocortin is a protein that in humans is encoded by the UCN gene. Urocortin belongs to the corticotropin-releasing factor (CRF) family of proteins which includes CRF, urotensin I, sauvagine, urocortin II and urocortin III. Urocortin is involved in the mammalian stress response, and regulates aspects of appetite and stress response.

<span class="mw-page-title-main">Amrinone</span>

Amrinone, also known as inamrinone, and sold as Inocor, is a pyridine phosphodiesterase 3 inhibitor. It is a drug that may improve the prognosis in patients with congestive heart failure. Amrinone has been shown to increase the contractions initiated in the heart by high-gain calcium induced calcium release (CICR). The positive inotropic effect of amrinone is mediated by the selective enhancement of high-gain CICR, which contributes to the contraction of myocytes by phosphorylation through cAMP dependent protein kinase A (PKA) and Ca2+ calmodulin kinase pathways.

Neuromedin U is a neuropeptide found in the brain of humans and other mammals, which has a number of diverse functions including contraction of smooth muscle, regulation of blood pressure, pain perception, appetite, bone growth, and hormone release. It was first isolated from the spinal cord in 1985, and named after its ability to cause smooth muscle contraction in the uterus.

<span class="mw-page-title-main">Corticotropin-releasing hormone receptor 1</span> Protein-coding gene in the species Homo sapiens

Corticotropin-releasing hormone receptor 1 (CRHR1) is a protein, also known as CRF1, with the latter (CRF1) now being the IUPHAR-recommended name. In humans, CRF1 is encoded by the CRHR1 gene at region 17q21.31, beside micrototubule-associated protein tau MAPT.

<span class="mw-page-title-main">Corticotropin-releasing hormone receptor 2</span> Protein-coding gene in the species Homo sapiens

Corticotropin-releasing hormone receptor 2 (CRHR2) is a protein, also known by the IUPHAR-recommended name CRF2, that is encoded by the CRHR2 gene and occurs on the surfaces of some mammalian cells. CRF2 receptors are type 2 G protein-coupled receptors for corticotropin-releasing hormone (CRH) that are resident in the plasma membranes of hormone-sensitive cells. CRH, a peptide of 41 amino acids synthesized in the hypothalamus, is the principal neuroregulator of the hypothalamic-pituitary-adrenal axis, signaling via guanine nucleotide-binding proteins (G proteins) and downstream effectors such as adenylate cyclase. The CRF2 receptor is a multi-pass membrane protein with a transmembrane domain composed of seven helices arranged in a V-shape. CRF2 receptors are activated by two structurally similar peptides, urocortin II, and urocortin III, as well as CRH.

<span class="mw-page-title-main">CRHBP</span>

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<span class="mw-page-title-main">UCN2</span>

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<span class="mw-page-title-main">Verucerfont</span>

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Sauvagine is a neuropeptide from the corticotropin-releasing factor (CRF) family of peptides and is orthologous to the mammalian hormone, urocortin 1, and the teleost fish hormone, urotensin 1. It is 40 amino acids in length, and has the sequence XGPPISIDLSLELLRKMIEIEKQEKEKQQAANNRLLLDTI-NH2, with a pyrrolidone carboxylic acid modification at the N-terminal and amidation of the C-terminal isoleucine residue. It was originally isolated from the skin of the frog Phyllomedusa sauvagii. Given its relation to other CRF-related peptides, it exerts similar physiological effects as corticotropin-releasing hormone.

References

  1. 1 2 3 4 5 Smani T, Calderon E, Rodriguez-Moyano M, Dominguez-Rodriguez A, Diaz I, Ordóñez A (2011). "Urocortin-2 induces vasorelaxation of coronary arteries isolated from patients with heart failure". Clinical and Experimental Pharmacology & Physiology. 38 (1): 71–6. doi:10.1111/j.1440-1681.2010.05466.x. PMID   21105894. S2CID   34132312.
  2. 1 2 3 4 5 Nishikimi T, Miyata A, Horio T, Yoshihara F, Nagaya N, Takishita S, Yutani C, Matsuo H, Matsuoka H, Kangawa K (2000). "Urocortin, a member of the corticotropin-releasing factor family, in normal and diseased heart" (PDF). American Journal of Physiology. Heart and Circulatory Physiology. 279 (6): H3031–9. doi:10.1152/ajpheart.2000.279.6.h3031. PMID   11087261. S2CID   14876819.
  3. 1 2 Kumar V, Abbas AK, Fausto N, Mitchell RN, Burns D (2007). "From The Heart". In Kumar V, Abbas AK, Fausto N, Mitchell RN (eds.). Robbins Basic Pathology (8th ed.). Philadelphia PA: Saunders. pp. 379–419.
  4. 1 2 Davis ME, Pemberton CJ, Yandle TG, Fisher SF, Lainchbury JG, Frampton CM, Rademaker MT, Richards M (2007). "Urocortin 2 infusion in human heart failure". European Heart Journal. 28 (21): 2589–97. doi: 10.1093/eurheartj/ehm340 . PMID   17720993.
  5. 1 2 Meili-Butz S, Bühler K, John D, Buser P, Vale WW, Peterson KL, Brink M, Dieterle T (2010). "Acute effects of urocortin 2 on cardiac function and propensity for arrhythmias in an animal model of hypertension-induced left ventricular hypertrophy and heart failure". European Journal of Heart Failure. 12 (8): 797–804. doi: 10.1093/eurjhf/hfq054 . PMID   20388649.
  6. 1 2 Bale TL, Hoshijima M, Gu Y, Dalton N, Anderson KR, Lee KF, Rivier J, Chien KR, Vale WW, Peterson KL (2004). "The cardiovascular physiologic actions of urocortin II: acute effects in murine heart failure". Proceedings of the National Academy of Sciences of the United States of America. 101 (10): 3697–702. Bibcode:2004PNAS..101.3697B. doi: 10.1073/pnas.0307324101 . PMC   373525 . PMID   14990799.
  7. 1 2 3 4 Yang LZ, Kockskämper J, Khan S, Suarez J, Walther S, Doleschal B, Unterer G, Khafaga M, Mächler H, Heinzel FR, Dillmann WH, Pieske B, Spiess J (January 2011). "cAMP- and Ca²(+) /calmodulin-dependent protein kinases mediate inotropic, lusitropic and arrhythmogenic effects of urocortin 2 in mouse ventricular myocytes". British Journal of Pharmacology. 162 (2): 544–56. doi:10.1111/j.1476-5381.2010.01067.x. PMC   3031072 . PMID   20942811.
  8. 1 2 3 4 Yang LZ, Tovote P, Rayner M, Kockskämper J, Pieske B, Spiess J (April 2010). "Corticotropin-releasing factor receptors and urocortins, links between the brain and the heart". European Journal of Pharmacology. 632 (1–3): 1–6. doi:10.1016/j.ejphar.2010.01.027. PMID   20132811.
  9. 1 2 3 4 5 Yang LZ, Kockskämper J, Heinzel FR, Hauber M, Walther S, Spiess J, Pieske B (February 2006). "Urocortin II enhances contractility in rabbit ventricular myocytes via CRF(2) receptor-mediated stimulation of protein kinase A". Cardiovascular Research. 69 (2): 402–11. doi: 10.1016/j.cardiores.2005.10.015 . PMID   16386238.
  10. ↑ Smani T, Domínguez-Rodríguez A, Hmadcha A, Calderón-Sánchez E, Horrillo-Ledesma A, Ordóñez A (2007). "Role of Ca2+-independent phospholipase A2 and store-operated pathway in urocortin-induced vasodilatation of rat coronary artery". Circulation Research. 101 (11): 1194–203. doi: 10.1161/CIRCRESAHA.107.159053 . PMID   17885217.
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