Identification of α-Subunits of Trimeric GTP-Binding Proteins in Human Platelets by RT-PCR

Willigen, Gijsbert van; Donath, J.; Lapetina, Eduardo G.; Akkerman, J. W. N.

doi:10.1006/bbrc.1995.2282

Cited by 35 publications

(21 citation statements)

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“…Hematopoiesis appears normal in single and double Gq class KO mice. Differential expression of G␣15/G␣16 in hematopoietic cells according to their maturational stage (2,16,32,33) suggested that hematopoiesis might be altered in the G␣15 Ϫ/Ϫ mice. Therefore, we characterized the cellular composition of hematopoietic tissues of G␣15 Ϫ/Ϫ mice by FAC Scan analysis.…”

Section: Intercrossing Heterozygous G␣15mentioning

confidence: 99%

Normal Hematopoiesis and Inflammatory Responses Despite Discrete Signaling Defects in Gα15 Knockout Mice

Davignon

Catalina

Smith³

et al. 2000

Molecular and Cellular Biology

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G␣15 activates phospholipase C␤ in response to the greatest variety of agonist-stimulated heptahelical receptors among the four Gq class G-protein ␣ subunits expressed in mammals. G␣15 is primarily expressed in hematopoietic cells in fetal and adult mice. We disrupted the G␣15 gene by homologous recombination in embryonic stem cells to identify its biological functions. Surprisingly, hematopoiesis was normal in G␣15 ؊/؊ macrophages. Despite discrete signaling defects, compensation by coexpressed Gq and/or Gi class ␣ subunits may suppress abnormalities in G␣15-deficient mice.Heterotrimeric G proteins transduce signals from ligandactivated seven-transmembrane domain receptors to effector proteins that regulate the release of intracellular second messengers, such as Ca 2ϩ and cyclic AMP. A diverse family of G-protein-coupled receptors bind numerous hormones and neurotransmitters, peptides, small proteins, and lipid molecules. The biological functions mediated by G proteins are equally diverse, including behavioral and sensory functions, appetite control, arousal, metabolism, development, inflammation, and chemotaxis.Heterotrimeric G proteins are composed of ␣ and ␤␥ subunits that can independently regulate effector proteins. Mammals express 16 distinct G␣ subunit genes that are grouped in four classes, Gq, Gi, Gs, and G12, according to sequence similarity, effector regulation, and responsiveness to RGS (regulators of G-protein signaling) proteins, a recently identified family of GTPase-activating proteins (GAPs) for G␣ subunits (30). The Gq class ␣ subunits activate all isoforms of phospholipase C␤ (PLC␤), which hydrolyze the membrane lipid phosphatidylinositol-4,5-bisphosphate to produce inositol trisphosphate and diacylglycerol. PLC␤2 and PLC␤3 are also activated by G␤␥ subunits, primarily released from Gi class G proteins (31), which is the basis for pertussis toxin inhibition of PLC␤ activity and Ca 2ϩ signaling evoked by Gi-coupled receptors (2, 20). Inositol trisphosphate produced by the activity of PLC␤ evokes calcium release from intracellular stores, and diacyl-

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Section: Intercrossing Heterozygous G␣15mentioning

confidence: 99%

Normal Hematopoiesis and Inflammatory Responses Despite Discrete Signaling Defects in Gα15 Knockout Mice

Davignon

Catalina

Smith³

et al. 2000

Molecular and Cellular Biology

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“…[27][28][29] Studies in knockout mice have established that G␣ i2 and G␣ z play a critical role in modulating adenylate cyclase activity and platelet aggregation in response to ADP and adrenaline, respectively. 25,29 Moreover, at least in mice, G␣ i2 and G␣ z are the predominant subtypes coupled to the P2Y 12 and ␣ 2A -adrenergic receptors, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…27,28 Because these subfamily members can all inhibit cAMP formation by adenylate cyclase, we examined the levels of expression of these different subtypes in membranes prepared from normal and patient platelets. Immunoblots were probed with specific antisera against G␣ i1 , G␣ i2 , G␣ i3 , and G␣ z .…”

Section: The Effect Of Adrenaline On Aggregation Responses Stimulatedmentioning

confidence: 99%

Evidence for a role for Gαi1 in mediating weak agonist-induced platelet aggregation in human platelets: reduced Gαi1 expression and defective Gi signaling in the platelets of a patient with a chronic bleeding disorder

Patel

Rahman

et al. 2003

Blood

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We have examined platelet functional responses and characterized a novel signaling defect in the platelets of a patient suffering from a chronic bleeding disorder. Platelet aggregation responses stimulated by weak agonists such as adenosine diphosphate (ADP) and adrenaline were severely impaired. In comparison, both aggregation and dense granule secretion were normal following activation with high doses of collagen, thrombin, or phorbol-12 myristate-13 acetate (PMA). ADP, thrombin, or thromboxane A 2 (TxA 2 ) signaling through their respective G qcoupled receptors was normal as assessed by measuring either mobilization of intracellular calcium, diacylglycerol (DAG) generation, or pleckstrin phosphorylation. In comparison, G i -mediated signaling induced by either thrombin, ADP, or adrenaline, examined by suppression of forskolin-stimulated rise in cyclic AMP (cAMP) was impaired, indicating dysfunctional G␣ i signaling. Immunoblot analysis of platelet membranes with specific antiserum against different G␣ subunits indicated normal levels of G␣ i2 , G␣ i3 , G␣ z , and G␣ q in patient platelets. However, the G␣ i1 level was reduced to 25% of that found in normal platelets. Analysis of platelet cDNA and gDNA revealed no abnormality in either the G␣ i1 or G␣ i2 gene sequences.

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“…Mutations in the Gsa gene have been discovered in some human disorders, such as pituitary adenomas, thyroid adenoma, acromegaly, and a form of inherited hormone resistance termed pseudohypoparathyroidis m (Albright hereditary osteodystrophy) (4)(5)(6)(7)(8)(9)(10)(11)(12). In addition to the multiple mutations, several examples of alternative splicing, including aberrant splicing, of Gsa transcript are now known (13)(14)(15)(16)(17)(18). Originally four forms of Gsa (Gsa -1 to -4) was isolated and shown to be splicing products of a single gene, resulting from alternative use of exon 3 (and/or) use of the trinucleotide CAG (3).…”

Section: Introductionmentioning

confidence: 99%

Existence of Multiple Novel Gsalpha Splice Variants in Acute Leukemia Patients

Ye¹,

Lü

Zhang

et al. 1999

IUBMB Life

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SummaryThe ® subunit of the stimulatory G protein, Gs®, is involved in stimulation of the adenylate cyclase pathway of signal transduction. In this study, we investigated the status of the Gs® gene in 29 acute leukemia patients and identi ed three novel splice variants (designated Gs®L-1,Gs®L-2, and Gs®L-3), possibly derived from aberrant splicing. All of the splice variants have in-frame deletions, removing the functional domain responsible for GTPase activity of Gs®, and would encode truncated proteins of 160(Gs®L-1), 90(Gs®L-2) and 70(Gs®L-3) amino acids, respectively. The data suggest that these novel products may be implicated in an as-yetunidenti ed signal transduction pathway in hematopoietic cells. IUBMB Life, 48: 299-304, 1999

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Identification of α-Subunits of Trimeric GTP-Binding Proteins in Human Platelets by RT-PCR

Cited by 35 publications

References 0 publications

Normal Hematopoiesis and Inflammatory Responses Despite Discrete Signaling Defects in Gα15 Knockout Mice

Normal Hematopoiesis and Inflammatory Responses Despite Discrete Signaling Defects in Gα15 Knockout Mice

Evidence for a role for Gαi1 in mediating weak agonist-induced platelet aggregation in human platelets: reduced Gαi1 expression and defective Gi signaling in the platelets of a patient with a chronic bleeding disorder

Existence of Multiple Novel Gsalpha Splice Variants in Acute Leukemia Patients

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