Connexins (Cx) (TC# 1.A.24), or gap junction proteins, are structurally related transmembrane proteins that assemble to form vertebrate gap junctions. An entirely different family of proteins, the innexins, form gap junctions in invertebrates.[1] Each gap junction is composed of two hemichannels, or connexons, which consist of homo- or heterohexameric arrays of connexins, and the connexon in one plasma membrane docks end-to-end with a connexon in the membrane of a closely opposed cell. The hemichannel is made of six connexin subunits, each of which consist of four transmembrane segments. Gap junctions are essential for many physiological processes, such as the coordinated depolarization of cardiac muscle, proper embryonic development, and the conducted response in microvasculature. For this reason, mutations in connexin-encoding genes can lead to functional and developmental abnormalities.

1. “Connexins as Key Mediators of Endocrine Function”
College of Health Sciences
School of Medicine
Department of Medical Physiology
P.by: Habtemariam Mulugeta
ID No. GSR/2895/14
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Habtemariam M.

2. “Connexins as Key Mediators of Endocrine Function”
Advanced Endocrinology
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Outline
 Objectives
 Introduction
 Nomenclature of Cx
 Biosynthesis of Cx
 Functions of Cx
 Cx & implications in Disease
 Summary
 Acknowledgement
 References
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Objectives
 After completing this session, students should be able to:
Describe briefly about Connexin.
Explain about the Biosynthesis of Connexins.
Differentiate the Nomenclature of Connexins.
Appreciate the Function of Connexins.
Familiarize with the implications of Connexin in Disease.
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Introduction
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 Connexins (Cx) or gap junction proteins, are structurally related transmembrane
proteins that assemble to form vertebrate gap junctions.
 The Human Cx family comprise 21 members.
 Each Cx is coded by a different gene.
 The phylogenetic tree of the Cx genes reveals that they are part of 5 distinct sub-
groups, referred to as α, β, γ, δ, & ε respectively.
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Cont.
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Figure 1: The phylogenetic tree of the connexin genes.
Table 1: The family of connexins

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Cont.
 Cx contain 4 highly ordered Transmembrane Segments (TMSs):
 Primarily unstructured C & N cytoplasmic Termini,
 Cytoplasmic loop (CL) and
 2 extra-cellular loops, (EL-1) and (EL-2).
 Cx are assembled in Groups of 6 to form Hemichannels & 2 Hemichannels
then combine to form a Gap Junction.
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Cont.
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Figure 2: Connexon and connexin structure

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Nomenclature of Cx
 Cx Nomenclature, where Cx are commonly named according to their
molecular weights.
 e.g. Cx26 is the Cx protein of 26 kDa.
 Gap Junction Protein System (GJ), where Cx are sorted by their sub-groups
like α (GJA) & β (GJB) forms, followed by an identifying number,
 e.g. GJB2  Cx26
 1 kilodaltons = 1.6605402E-18 milligrams
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Biosynthesis of Cx
 Cx translated by ribosomes, then Cx are inserted into ER membrane.
 In the ER: Cx are properly folded, yielding EL-1 & EL-2.
 Followed by Oligomerization of Cx molecules into Hemichannels between the ER and
trans-Golgi network (depending on the Cx type).
 Which are then delivered to the cell membrane (CM) via the Actin or Microtubule networks.
 Connexons may also be delivered to the CM by direct transfer from the rough ER.
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Cont.
 Upon insertion into the CM, connexons may remain as hemichannels or they dock with
compatible connexons on adjacent cells to form gap junctions.
 Newly delivered connexons are added to the periphery of pre-formed gap junctions.
 The central "older" gap junction fragment are degraded by internalization of annular junction
into one of the two cells.
 Subsequent lysosomal or proteasomal degradation occurs, or in some cases the connexons are
recycled to the membrane.
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Cont.
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Figure 2: Life cycle and protein
associations of connexins.
Hanaa Hariri for Dbouk et al., 2009.

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Functions of Cx
 Cx have multifaceted contributions to Brain Development & specific processes in the
neuro-glio-vascular unit, including:
 Synaptic transmission & plasticity,
 Glial Signaling,
 Blood-brain Barrier integrity in the mature CNS.
 CNS: GJ provide electrical coupling between progenitor cells, neurons, & glial cells.
 Energy status of a cell could be controlled via Cx expression and channel formation.
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Cont.
 The functioning of muscle cells.
 Vasomotor Control
 Conducted response in microvasculature.
 Cell-cell Adhesion, Interactions with the Cytoskeleton, & the Activation of
Intracellular Signaling Pathways.
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Cont.
 Retina: adapting the visual function for various lighting conditions.
 Cx – GJCs enable direct cell-cell communication of small molecules.
 Cx hemichannels contribute to autocrine/paracrine signaling pathways.
 Development
 Embryonic Development,
 Morphogenesis, & Cell Differentiation,
 Control of Adult Cell Proliferation & Migration,
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Cont.
 Resistance to Cytotoxic Agents.
 Compensation of Enzymatic Defects and Metabolic cooperation.
 Electrical & Mechanical Synchronization.
 Hormonal Transmission.
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Cont.
 Exocrine Secretion
 Cx: obligatory features of adult secretory cells of endocrine and exocrine glands
 Cx: mediate, but not necessary for secretion to occur but are required for its fine
regulation, in terms of biosynthesis, storage, & release of many secretory products.
 The secretory cells of most multicellular, endocrine glands express only one
Cx isoform of either the α or γ group.
 Cx43 is the most widespread isoform.
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Cont.
 Exocrine glands: secretory cells express Cx32, often co-expressed with
Cx26, whichever the type of secretion they produce.
 Few endocrine cells and most endocrine neurons have selected Cx36,
whereas Cx40 is so far restricted to the renin-producing cells of kidney.
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Cont.
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Table 2: The connexins of endocrine and exocrine glands

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Cont.
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Cx & implications in Disease
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Table 3: The connexins function and implications in disease

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Cont.
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Summary
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 Cx or GJ proteins, are structurally related transmembrane proteins that assemble to form
vertebrate gap junctions.
 The secretory cells of endocrine glands express only one Cx isoform of either the α or γ group.
 Cx43 is the most widespread isoform.
 Cx: obligatory features of adult secretory cells of endocrine and exocrine glands.
 Cx required for its fine regulation, in terms of biosynthesis, storage, & release of many
secretory products.

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Acknowledgement
 Firstly, I would like Thanks our Lord and Savior Jesus Christ Son of the True Living God,
with his Most Holy Mother Theotokos and all the Saints.
 Next my deepest gratitude goes to my instructor Dr. Dresbachew who gave me this
chance to prepare and present on “Connexins as Key Mediators of Endocrine Function.”
 Finally, I would like to thank my family & friends for their support of my works.
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References
 Dbouk HA, Mroue RM, El-Sabban ME, Talhouk RS (March 2009). “Connexins: a myriad of functions extending beyond
assembly of gap junction channels” Cell Commun Signal. 7: 4. doi:10.1186/1478-811X-7-4.
 Lodish, Harvey F.; Arnold Berk; Paul Matsudaira; Chris A. Kaiser; Monty Krieger; Mathew P. Scott; S. Lawrence Zipursky;
James Darnell (2004). Molecular Cell Biology (5th ed.). New York: W.H. Freeman and Company. pp. 230–1. ISBN 0-7167-
4366-3.
 Maeda S, Nakagawa S, Suga M, Yamashita E, Oshima A, Fujiyoshi Y, Tsukihara T (April 2009). "Structure of the connexin 26
gap junction channel at 3.5 A resolution". Nature. 458 (7238): 597–602. doi:10.1038/nature07869. ISSN 1476-4687. PMID
19340074. S2CID 4431769.
 Ayad WA, Locke D, Koreen IV, Harris AL (June 2006). "Heteromeric, but not homomeric, connexin channels are selectively
permeable to inositol phosphates". J. Biol. Chem. 281 (24): 16727–39. doi:10.1074/jbc.M600136200. ISSN 0021-9258. PMID
16601118.
 Laird DW (March 2006). "Life cycle of connexins in health and disease". Biochem. J. 394 (Pt 3): 527–43.
doi:10.1042/BJ20051922. PMC 1383703. PMID 16492141.
 Bennett MV, Zukin RS (February 2004). "Electrical coupling and neuronal synchronization in the Mammalian brain". Neuron.
41 (4): 495–511. doi:10.1016/s0896-6273(04)00043-1. PMID 14980200. S2CID 18566176.
 http://www.prv.org
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