Cell Biology 16Cell Biology 16- Intercellular signaling- Intercellular signaling

Sung Youn Lee, PhD. StudentSung Youn Lee, PhD. StudentVeterinary collage, Room 320Veterinary collage, Room 32002 450 3719, 016 293 605902 450 3719, 016 293 6059

leevet@paran.comleevet@paran.com

Cell Signaling• Cell communication : why?

– Multicellular organism• Cell communication : how?

– A variety messengers– Endocrine(hormone), Paracrine, Neurotrans

mitter, Autocrine

Hormones and Endocrine signaling

• Classification by nature– Steroid, protein, amino acids

• Classification by initial action– The location of receptor– Cell surface (in the membrane) ; protein, pept

ide and catecholamine (epinephrine and norepinephrine),

– Cytoplasm (steroid)– Nucleus (thyroxine)

Hormonal secretion• Regulated exocytosis – special secretor

y vesicle• Ligand and surface receptor binding• Ca2+ rising --> triger the fusion of vesicl

e and plasma membrane

Steroid hormone• Similar to that of cholesterol

– Adrenal cortex : cortisol & aldosterone– Ovaries : estrogen & progesterone– Testes : testosterone(androgen)– Placenta : estrogen & progesterone

Neurosecretory cell• Resemble both endocrine cells and neuron

s (dual properties)• Hypothalamus

– TRH (thyrotropin releasing hormone)– GnRH (gonadotropin releasing hormone)– CRH (corticotropin releasing hormone)– GRH (growth hormone releasing hormone)– These reach the pituitary and supress or stimul

ate the release of a secondary hormones.

Neurosecretory cell• Hypothalamus

– Peptidergic (peptide-secreting) neuroendocrine cells extend axons into the posterior pituitary

• Pituitary p.• Vasopressin - BP△ (by vasoconstriction and water

resorption by kidney)• Oxytocin – uterus contraction and lactation (smoot

h muscle contraction)• Angiotensin II - thirst• Cholecystokinin - eating

Neurosecretory cell• Pituitary a.

• Growth hormone• ACTH (adrenocorticotropic hormone)• Thyroid-stimulating hormone• Follicle-stimulating hormone• Luteinizing hormone• Prolactin

Drawings by Leonardo da Vinci (1508-1509)

(A) Detail from the fresco, "Creation of Adam," by Michelangelo Buonarroti, 1508-1512 (B) The contour of the same image is reminiscent of a midline saggital section of the brain and includes the hypothalamus, pituitary and brainstem. (From Toni R., The human hypothalamus: clinical anatomy of endocrine, autonomic and behavioral responses, J. Endocrinol. Invest 2003, in press).

Adrenal cortex : corticoid (mineralocorticoid and glucocorticoid)Adrenal medulla : catecholamines (epinephrine and norepinephrine)

Zona glomerulosa -aldosterone (mineralocorticoid)

Zona fasiculata and reticularis - cortisol and cortisone (glucotorticoid)

Paracrine communication• Do not enter the circulation• Highly localized

Growth factors• Soluble polypeptides• All cells make polypeptide growth factors• Function : mitogen, trophic factors, chemoattractants• 10-30 kDa, more than 100 (Table 7-2)• Ex, PDGF platelet-dervied growth factor

– Mitogen and trophic factors ; fibroblast & smooth muscle cells

– Chemoattractants ; fibrolasts & macrophages (blood clotting)

Growth factors

Activates a different signal transduction pathways

Pleotropic response in a single cell

Switch mitogen to trophic stimulus

Blast stage Mature

Nerve growth factor• Require for survival and differentiation• 50% neurons < die normally (excess innervati

on to target ; why? - Assured)• Nerve growth factors (NGF)

– chemoattractant molecules– Homodimer – two 118 a.a. chains coupled by disu

lfied bond

50%< die

Nerve growth factor• NGF binds to NGF receptors on the growth co

nes of approaching axons.• It is internalized by receptor mediated endocyt

osis and transported retrogradely to the cell body, where it undergoes lysosomal degradation.

• NGF supports the survival of cholinergic nerons.– Alzheimer disease (cholinergic neuron for memory)

팀 동료인 베이브 루스와 함께 1 루수를 맡으며 메이저리그 역사상 가장 견고한 1, 2 번을 구축했다는 평을 받는다 . 한 시즌 100 득점 이상을 13 시즌 연속으로 수립하였고 , 150 타점 이상을 7 번이나 기록하였으며 , 1932 년에는 한경기에 4연속 홈런을 때려 20 세기 들어 첫번째 선수가 되는 영광도 누렸다 .역대 타점 랭킹 1, 2 위 선수들이 21-23 시즌에 2200 타점을 넘어섰지만 루 게릭은 단 14 시즌동안 1995 타점을 기록하였다 . 이 외에 12 년 연속 3 할 타율 , 13 년 연속 100 타점 -100 득점 , 최다 400 총루타 5 회 , 사이클링 히트 2 회도 그의 이름을 드높이는 결과이다 .근위축성 측색 경화증 (ALS) 이란 희귀병에 걸려 사망하였는데 , 이후 이 병은 그의 이름을 따 ' 루 게릭병 ' 으로 명명되어 그의 아까운 죽음을 기리고 있다 .

Nerve growth factor• Lou Gehrig’s disease• = ALS (amyotrophic lateral sclerosis)• CNTF (ciliary neurotrophic factor)

– PNS : schwann cell– CNS : astrocyte– Cf. other neurotrophic factors are secreted by targ

et cell (muscle cell)– --> motor neuron ▽--> muscle▽

No NGF

50 ng/ml NGF

Nerve growth factor• Programmed cell death : how?

– Can prevent PCD with protein and mRNA systhesis inhibitor

– Ex, cycloheximide and actinomycin D– ==> autolytic enzyme

Extracellular matrix• Growth factors

– Most of them are soluble peptides, not all

– There is growth factors that attached to cell membrane or matrix

1) Low affinity receptors bind to-free heparin-heparan sulfate chain

2) Comformational change by proteoglycan

3) High affinity receptors

4) Prolongs the resistance of HBGF

5) Regeneration and/or carcinogenesis

Autocrine• PDGF : cytotrophoblast – placenta• IL-2 : T helper cell• These are mitogen.

PDGF

Histamine• Mast cell reside in the connective tissu

e throughout the body.• They have IgE receptor and histamine in

their secretory vesicle.

Ecosanoids• Ecosanoid ; 20-carbon polyunsaturated fatty

acids (prostaglandins, thromboxanes, leukotrienes, and other active metabolites)

• Highly diffusible through membrane.• Biological effects of PGs

– Smooth muscle contraction / platelet aggregation / uterine contraction / cause inflammation (nociceptor-pain)

– Aspirin, indomethacin and NSAID

Asprin, Ibupropen, Indomethacin

steroid

NO nitric oxide• Highly diffusible through membrane.• Biological effects of NO

– Memory in brain– Relaxation of blood vessel

• Mechanism of vasodilation– Endothelial cell contain NO synthase (Fig 7-16)– Ach binds muscarinic receptor on the surface of endothelial cell– G protein mediated signal transduction– Ca2+ increase– NO synthase

– Nitroglycerin is rapidly converted to NO in the blood

Synaptic transmission

Ach

EpinehprineNorepinephrine

Ach Ach

Symphathetic

Parasymphathetic

Ach

Ach Ach-muscarinic-nicotinic

EpinehprineNorepinephrineAch : sweat glands and vasodilation (skeletal muscle)

Muscarinic Acetylcholine Receptors

M1 M2 M3 M4 M5

Distribution

Cerebral cortex,

hippocampus

HeartExocrine

glands, GI tract

Neostriatum Substantia nigra

Antagonists Pirenzepine AF-DX 116 pF-HHSiD

Agonists Xanomeline, CDD-0097

G protein Gq/11 Gi/o Gq/11 Gi/o Gq/11

Intracellular response

Phospholipase C

Adenylyl cyclase inhibitio

n

Phospholipase C

Adenylyl cyclase inhibitio

n

Phospholipase C

Nicotinic Acetylcholine ReceptorsReceptor Skeletal

muscleAutonomic ganglion CNS CNS

Subunits 1,1,,() 3,5,7,2,4 3,4,2,4 7,8,9

-Bungarotoxin + +/- - +

Antagonists -Bungarotoxin Hexamethonium

Dihydro--erythroidine -Bungarotoxin

Mecamylamine Mecamylamine

Agonists Epibatidine Epibatidine

Epibatidine

ABT-418

Two forms of synapse

Speed : heart and gut1 msec delay

Chemical neurotransmitter

• Fast-acting neurotransmitters– Acetylcholine– GABA(γ-amino butyric acid)– Glycine– Glutamate

• Slow-acting neurotransmitters– Catecholamine (dopamine, norepi, epi)– Indoleamine (serotonin, histamine)– Various neuropeptides

Directly open the channel

Indirectly open the channel

Different messengers localized to different

types of vesicle in nerve terminals

Vesicle Small LargeSize 50nm 90-250nmShape lucent denseVelocity Fast a. Slow a.

The skeletal neurouscular junction

Synaptic vesicle• ~ 5,000 molecules/vesicle• MEP miniature synaptic potential --

> single synaptic vesicle release• 1mV• With Ca2+

Multiple synaptic inputs converge on a single

neuron• Na+/Cl-• Excitatory/Inhibitory• Integration• EPSP excitatory p s p• IPSP inhibitory p s p

Thank you for your attention ~Thank you for your attention ~