Signal Transduction (IND 447)

Receptors, G Proteins and Human Disease

Website with GPCR mutations:
http://tinygrap.uit.no/queryform10.html

Course Handouts and Slides:

GPCR's and Disease Handout (1/29/2004)

GPCR's and Disease Slides (1/29/2004)

Protein Kinase C Regulation Handout (2/3/2004)

Protein Kinase C Regulation Slides (2/3/2004)

References for Course:

Barak LS, Oakley RH, Laporte, SA, and Caron MG. Proc. Natl. Acad. Sci. USA 98:93-98, 2001.

Farooqi IS, Keogh JM, Yeo GSH, Lank EJ, Cheetham T, and O'Rahilly S. N. Engl. J. Med. 348:1085-1095, 2003.

Nishiguchi KM, Sandberg MA, Kooijman AC, Martemyanov KA, Pott JWR, Hagstrom SA, Arshavsky VY, Berson EL, and Dryja TP. Nature 427:75-78.

Rana BK, Shiina T, and Insel PA. Annu. Rev. Pharmacol. Toxicol. 41:593-624, 2001.

Research Papers

Violin JD, Zhang J, Tsien RY, and Newton AC (2003) A genetically encoded fluorescent reporter reveals oscillatory phosphorylation by protein kinase C. J Cell Biol 161:899-909. Required

Nishikawa K, Toker A, Johannes F-J, Songyang Z, and Cantley LC (1997) Determination of the specific substrate sequence motifs of protein kinase C isozymes. J Biol Chem 272:952-960.

Mochly-Rosen D, Khaner H, and Lopez J (1991) Identification of intracellular receptor proteins for activated protein kinase C. Proc Natl Acad Sci USA 88:3997-4000.

Review Articles

Newton AC, (2003) Regulation of the ABC kinases by phosphorylation: protein kinase C as a paradigm. Biochem J 370:361-371. Recommended

Schechtman D and Mochly-Rosen D (2001) Adaptor proteins in protein kinase C-mediated signal transduction. Oncogene 20:6339-6347 Recommended

References to some of the papers discussed in class:

Iiri, T, Herzmark, P., Nakamoto, J.M., Van Dop, C., and Bourne, H.R. Rapid GDP release from Gs alpha in patients with gain and loss of endocrine function. Nature. 1994 Sep 8;371(6493):164-8. Description of mutation causing testotoxicosis.

VanSande et al. Genetic basis of endocrine disease. Somatic and germline mutations of the TSH receptor gene in thyroid diseases. J. Clin. Endocrinol. and Metab. 80: 2577-2585, 1995. Summary of mutations in the thyroid TSH receptors.

Rodien P. et al.. Familial gestational hyperthyroidism caused by a mutant thyrotropin receptor hypersensitive to human chorionic gonadotropin. New Engl J Med 339:1823-6, 1998. TSH receptor mutation (K to R) in N terminus increasing sensitivity to hCG.

Samson M, Libert F, Doranz BJ et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382: 722-725, 1996. Resistance to HIV infection in patients with a mutation in the G protein coupled receptor that act as the co-receptor for HIV.

Frade JMR. Llorente M. Mellado M. Alcami J. Gutierrez-Ramos JC. Zaballos A. Real G. Martinez-A C. The amino-terminal domain of the CCR2 chemokine receptor acts as coreceptor for HIV-1 infection. J Clin. Invest. 100:497-502, 1997.

Nishiguchi KM, Sandberg MA, Kooijman AC, Martemyanov KA, Pott JW, Hagstrom SA, Arshavsky VY, Berson EL, Dryja TP. Defects in RGS9 or its anchor protein R9AP in patients with slow photoreceptor deactivation. Nature 427:75-78, 2004.

Some general references:

Rana BK, Shiina T, Insel PA. Genetic variations and polymorphisms of G protein-coupled receptors: functional and therapeutic implications. Annu Rev Pharmacol Toxicol. 2001;41:593-624. Good review focusing on receptor structure rather than disease.

Weinstein LS, Yu S, Warner DR, Liu J. Endocrine manifestations of stimulatory G protein alpha-subunit mutations and the role of genomic imprinting. Endocr Rev. 2001 Oct;22(5):675-705. Good review of complex genetics.

Lania A, Mantovani G, Spada A. G protein mutations in endocrine diseases. Eur J Endocrinol 2001 Nov;145(5):543-59.

Menon ST, Han M, Sakmar TP. Rhodopsin: structural basis of molecular physiology. Physiol Rev. 2001 Oct;81(4):1659-88. Goes into detail on rhodopsin structure including mutations that cause retinitis pigmentosa and other diseases.

Farfel Z, Bourne H R, Iiri T. Mechanisms of Disease: The Expanding Spectrum of G Protein Diseases. N Engl J Med 340: 1012-1020, 1999.

Spiegel, AM Defects in G protein-coupled signal transduction in human disease. Annu Rev Physiol 58: 143-170, 1996.

G-PROTEINS

Inactive or absent Gs (a subunit)
Pseudohypoparathyroidism--inherited mutation in Gs (one good, one nonfunctional as)
--Multiple endocrine abnormalities in cAMP regulated organs
--Occurs when bad gene inherited from mother

Pseudopseudohypoparathyroidism--clinically less severe syndrome, same as mutation in one Gs
--Occurs when bad gene inherited from father

Both conditions--as protein levels about half of normal

Complex imprinting--tissue specificity, splice variants

Constitutively active Gs (a subunit)
Tumors
--Mutations in as--block GTPase activity, cause constitutive activity as candidate oncogene (termed gsp)
--Activating mutations found in 40% of growth hormone secreting pituitary adenomas; found in other endocrine tumors including pituitary, thyroid

McCune Albright Syndrome
--Somatic mutation in as in early embryonic development
--Patients mosaic for for constitutively active Gs (as)

Temperature-sensitive as
"Testotoxicosis"
--Males have general features of pseudohypoparathyroidism and precocious puberty with a mutant as that is inactive at 37°C and constitutively active at testicular temperature

Constitutively active Gi a2
Tumors
--Mutations in ai2--block GTPase activity, cause constitutive activity
--ai2 candidate oncogene (termed gip)
--Activating mutations found in >30% of adrenal, ovarian tumors

RECEPTORS
(examples, not complete lists)

Mutations causing nonfunction receptors
(If these words all look the same to you, you have one!).
Growth hormone releasing hormone (GHRH) receptor
--Familial growth hormone deficiency

Thyroid stimulating hormone (TSH) receptor
--Causes TSH resistance; may be compensated and euthyroid or hypothyroid

Luteinizing hormone (LH) receptor
--Causes Leydig cell hypoplasia, resistance to LH, male pseudohermaphroditism

Follicle stimulating hormone (FSH) receptor
--Hypergonadotropic ovarian dysgenesis

Vasopressin (V2) receptor
--X-linked
--Causes nephrogenic diabetes insipidus
--Kidney cannot respond to vasopressin (ADH)

Calcium sensing receptor
--Receptor on parathyroid gland cannot sense extracellular calcium appropriately
--Causes inherited hypocalciuric hypercalcemia

Color pigments--color blindness
--Blue--1/100,000, not sex-linked
--Red, green--X-chromosome, 5-10% of males affected

Chemokine (CCR5) receptor
--No phenotype known except resistance to HIV infection

Change in ligand binding specificity
Thyroid stimulating hormone (TSH) receptor
--Hyperthyroidism of pregnancy, mutation increases affinity for human chorionic gonadotropin (hCG), which increases in pregnancy

Mutations Causing Constitutively Active Receptors
Rhodopsin
--Some forms of retinitis pigmentosa
--Some forms of stationary night blindness

Thyroid stimulating hormone (TSH) receptor
--Constitutively active receptor stimulates thyroid growth and hormone production
--Germline mutation causes familial nonautoimmune hyperthyroidism
--Somatic mutation causes toxic adenoma; present in 80% of toxic nodules

Calcium receptor
--Receptor on parathyroid cells constitutively active, turns off parathyroid hormone even if extracellular calcium is low
--One constitutively activee mutant receptor causes autosomal dominant hypocalcemia, two mutant receptors cause severe neonatal form

Luteinizing hormone (LH) receptor
--Leydig cells activated to produce testosterone independent of pituitary LH
--Causes precocious puberty in males

Parathyroid hormone (PTH)/PTHRP Receptor
--Jansen metaphyseal chondrodysplasia

Disease caused by antibodies that activate receptors
Thyroid stimulating hormone (TSH) receptor
--Grave's disease, an autoimmune disease causing the most common form of hyperthyroidism, is due to antibodies to the TSH receptor (3% of females)
--Most antibodies to the TSH receptor activate it, causing TSH-independent activation of thyroid growth and thyroid hormone production

Improper processing of receptors
Rhodopsin
--Some forms of retinitis pigmentosa
--Rhodopsin fails to undergo normal processing in ER and Golgi causing eventual destruction of retinal cells and blindness

Interaction of a natural antagonist with receptors
Melanocortin receptors MC1 and MC4
--Agouti peptide is a natural antagonist of melanocyte stimulating hormone (MSH)
--Mutations causing either overexpression or lack of expression of agouti peptide can affect MSH receptor function (coat coloration in animals)
--Inactivating or constitutively active MSH receptors also control coat color