RGS2 regulates signal transduction in olfactory neurons by attenuating activation of adenylyl cyclase III

Sinnarajah, Srikumar; Dessauer, Carmen W.; Srikumar, Deepa; Chen, Jun; Yuen, John; Yilma, Solomon; Dennis, John C.; Morrison, Edward E.; Vodyanoy, Vitaly; Kehrl, John H.

doi:10.1038/35059104

Cited by 243 publications

(183 citation statements)

References 23 publications

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“…In this respect, direct binding of RGS2, RGS3, RGS4, and GAIP to phospholipase Cb1 interferes with activated Gaq subunits (Hepler et al, 1997;Anger et al, 2004). Also, RGS2 and RGS 3 interact with adenylyl cyclases reducing cAMP production (Chatterjee et al, 1997;Sinnarajah et al, 2001). The direct association of RGS proteins with the intracellular domains of GPCRs could help to deactivate GaGTP subunits before they regulate their corresponding effectors.…”

Section: Discussionmentioning

confidence: 99%

The RGSZ2 Protein Exists in a Complex with μ-Opioid Receptors and Regulates the Desensitizing Capacity of Gz Proteins

Garzón

Rodríguez-Muñoz

López-Fando

et al. 2005

Neuropsychopharmacol

104

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The regulator of G-protein signaling RGS17(Z2) is a member of the RGS-Rz subfamily of GTPase-activating proteins (GAP) that efficiently deactivate GazGTP subunits. We have found that in the central nervous system (CNS), the levels of RGSZ2 mRNA and protein are elevated in the hypothalamus, midbrain, and pons-medulla, and that RGSZ2 is glycosylated in synaptosomal membranes isolated from CNS tissue. In analyzing the function of RGSZ2 in the CNS, we found that when the expression of RGSZ2 was impaired, the antinociceptive response to morphine and [D-Ala 2 , N-MePhe 4 , Gly-ol 5 ]-enkephalin (DAMGO) augmented. This potentiation involved m-opioid receptors and increased tolerance to further doses of these agonists administered 24 h later. High doses of morphine promoted agonist desensitization even within the analgesia time-course, a phenomenon that appears to be related to the great capacity of morphine to activate Gz proteins. In contrast, the knockdown of RGSZ2 proteins did not affect the activity of d receptor agonists, [D-Pen 2,5 ]-enkephalin (DPDPE), and [D-Ala 2 ] deltorphin II. In membranes from periaqueductal gray matter (PAG), both RGSZ2 and the related RGS20(Z1) co-precipitated with m-opioid receptors. While a morphine challenge reduced the association of Gi/o/z with m receptors, it increased their association with the RGSZ2 and RGSZ1 proteins. However, only Gaz subunits co-precipitated with RGSZ2. Doses of morphine that produced acute tolerance maintained the association of Ga subunits with RGSZ proteins even after the analgesic effects had ceased. These results indicate that both RGSZ1 and RGSZ2 proteins influence m receptor signaling by sequestering Ga subunits, therefore behaving as effector antagonists.

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Section: Discussionmentioning

confidence: 99%

The RGSZ2 Protein Exists in a Complex with μ-Opioid Receptors and Regulates the Desensitizing Capacity of Gz Proteins

Garzón

Rodríguez-Muñoz

López-Fando

et al. 2005

Neuropsychopharmacol

104

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“…While RGS2 can act as a GAP protein for Gα i and Gα S proteins (Ingi et al 1998;Sinnarajah et al 2001), it is the most potent RGS for Gαq, the Gα subunit pivotal for the signalling of most vasoconstrictors, including noradrenaline, AngII, endothelin-1, thromboxane, vasopressin and thrombin (Heximer et al 1997). RGS2 will not only attenuate Gαq-mediated vasoconstrictor signals, vasoconstrictors such as AngII can also stimulate RGS2 transcript expression, which will ultimately result in a further feedback inhibition of Gαq-mediated signals (Grant et al 2000).…”

Section: Genetic Variants Of the Regulator Of G Protein Signalling (Rmentioning

confidence: 99%

“…While one report failed to demonstrate an association between the Add1 460W allele and ischemic stroke (Morrison et al 2001), Psaty and co-workers reported an increased risk for combined hemorrhagic and ischemic stroke in carriers of the Add1 460W allele, although there was no association to hypertension itself (Psaty et al 2002). In the same study mentioned just above, Morrison and coworkers (2001) documented an increased frequency for subclinical strokes in carriers of the GNB3 T allele, again independent of an effect on blood pressure.…”

Section: Hypertension and Strokementioning

confidence: 99%

Genetics of arterial hypertension and hypotension

Rosskopf

Schürks

Rimmbach

et al. 2007

Naunyn-Schmied Arch Pharmacol

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Human hypertension affects affects more than 20% of the adult population in industrialized countries, and it is implicated in millions of deaths worldwide each year from stroke, heart failure and ischemic heart disease. Available evidence suggests a major genetic impact on blood pressure regulation. Studies in monogenic hypertension revealed that renal salt and volume regulation systems are predominantly involved in the genesis of these disorders. Mutations here affect the synthesis of mineralocorticoids, the function of the mineralocorticoid receptor, epithelial sodium channels and their regulation by a new class of kinases, termed WNK kinases. It has been learned from monogenic hypotension that almost all ion transporters involved in the renal uptake of Na + have a major impact on blood pressure regulation. For essential hypertension as a complex disease, many candidate genes have been analysed. These include components of the reninangiotensin-aldosterone system, adducin, β-adrenoceptors, G protein subunits, regulators of G protein signalling (RGS) proteins, Rho kinases and G protein receptor kinases. At present, the individual impact of common polymorphisms in these genes on the observed blood pressure variation, on risk for stroke and as predictors of antihypertensive responses remains small and clinically irrelevant. Nevertheless, these studies have greatly augmented our knowledge on the regulation of renal functions, cellular signal transduction and the integration of both. Together, this provides the basis for the identification of novel drug targets and, hopefully, innovative antihypertensive drugs.

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“…These proteins share the conserved ''RGS domain'' of Ϸ120 aa which is responsible for accelerating GTPase activity on the G protein ␣ subunit (4)(5)(6). RGS proteins are thought to play a central role in the physiological regulation of the G protein cycle, and their importance has been confirmed in the immune response (7) and sensory perception (8,9). To date, more than 20 mammalian RGS proteins have been identified.…”

mentioning

confidence: 99%

PIP ₃ inhibition of RGS protein and its reversal by Ca ²⁺ /calmodulin mediate voltage-dependent control of the G protein cycle in a cardiac K ⁺ channel

Ishii

Inanobe

Kurachi

2002

Proc. Natl. Acad. Sci. U.S.A.

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Regulators of G protein signaling (RGS) accelerate intrinsic GTP hydrolysis on ␣ subunits of trimeric G proteins and play crucial roles in the physiological regulation of G protein-mediated cell signaling. The control mechanisms of the action of RGS proteins per se are poorly clarified, however. We recently showed a physiological mode of action of a RGS protein in cardiac myocytes. The voltagedependent formation of Ca 2؉ ͞calmodulin facilitated the GTPase activity of RGS by an unidentified mechanism, which underlay the ''relaxation'' behavior of G protein-gated K ؉ (KG) channels. Here we report the mechanism which is the reversal by Ca 2؉ ͞calmodulin of phosphatidylinositol-3,4,5,-trisphosphate (PIP3)-mediated inhibition of RGS. Purified RGS4 protein alone inhibited GTP-induced KG channel activity in inside-out patches from atrial myocytes. The inhibitory effect of RGS4 was reduced by PIP3 and restored by addition of Ca 2؉ ͞calmodulin. The intracellular application of anti-PIP3 antibody abolished the RGS-dependent relaxation behavior of KG current in atrial myocytes. This study, therefore, reveals a general physiological control mechanism of RGS proteins by lipidprotein interaction. H eterotrimeric G proteins mediate different intracellular signaling cascades and regulate many cellular functions (1). Although numerous kinds of G protein-coupled receptors and effectors have been identified, the existence of regulators of the G protein cycle has been neglected for a long period. Recently, a family of cytosolic proteins named ''regulators of G protein signaling'' (RGS proteins) has been identified (2, 3). These proteins share the conserved ''RGS domain'' of Ϸ120 aa which is responsible for accelerating GTPase activity on the G protein ␣ subunit (4-6). RGS proteins are thought to play a central role in the physiological regulation of the G protein cycle, and their importance has been confirmed in the immune response (7) and sensory perception (8, 9). To date, more than 20 mammalian RGS proteins have been identified. These RGS proteins vary in their molecular structure, tissue distribution, and intracellular localization, and thus may play divergent functional roles in different tissues.We recently found that RGS proteins were responsible not only for the acceleration of the deactivation time course upon agonist washout (10), but also for the characteristic gating behavior of G protein-activated inward-rectifier K ϩ channels (K G ) in cardiac atrial myocytes (11-13). K G channels are directly activated by the ␤␥ subunits released from pertussis toxinsensitive G proteins upon receptor stimulation, and contribute to acetylcholine (ACh)-induced deceleration of heart beat and neurotransmitter-evoked slow inhibitory postsynaptic potentials in neurons (14). When membrane potential is suddenly hyperpolarized from positive potentials, the K G current in myocytes first instantaneously and then slowly increases. The latter timedependent current change is termed ''relaxation'' and is characteristic for native K G current (15). ...

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RGS2 regulates signal transduction in olfactory neurons by attenuating activation of adenylyl cyclase III

Cited by 243 publications

References 23 publications

The RGSZ2 Protein Exists in a Complex with μ-Opioid Receptors and Regulates the Desensitizing Capacity of Gz Proteins

The RGSZ2 Protein Exists in a Complex with μ-Opioid Receptors and Regulates the Desensitizing Capacity of Gz Proteins

Genetics of arterial hypertension and hypotension

PIP ₃ inhibition of RGS protein and its reversal by Ca ²⁺ /calmodulin mediate voltage-dependent control of the G protein cycle in a cardiac K ⁺ channel

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RGS2 regulates signal transduction in olfactory neurons by attenuating activation of adenylyl cyclase III

Cited by 243 publications

References 23 publications

The RGSZ2 Protein Exists in a Complex with μ-Opioid Receptors and Regulates the Desensitizing Capacity of Gz Proteins

The RGSZ2 Protein Exists in a Complex with μ-Opioid Receptors and Regulates the Desensitizing Capacity of Gz Proteins

Genetics of arterial hypertension and hypotension

PIP 3 inhibition of RGS protein and its reversal by Ca 2+ /calmodulin mediate voltage-dependent control of the G protein cycle in a cardiac K + channel

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PIP ₃ inhibition of RGS protein and its reversal by Ca ²⁺ /calmodulin mediate voltage-dependent control of the G protein cycle in a cardiac K ⁺ channel