Protein , association subunits

The antimuscarinic drug atropine, and its derivative ipratropiumbromide, can also be used for antiarrhyth-mic treatment. Muscarinic receptors (M2 subtype) are mainly present in supraventricular tissue and in the AV node. They inhibit adenylylcyclase via G proteins and thereby reduce intracellular cAMP. On the other hand, activation of the M2 receptor leads to opening of hyperpolarizing Ik.acii and inhibits the pacemaker current If probably via the (3y-subunit of the Gi protein associated with this receptor. The results are hyperpolarization and slower spontaneous depolarization. Muscarinic receptor antagonists like atropine lead to increased heart rate and accelerated atrioventricular conduction. There are no or only slight effects on the ventricular electrophysiology. 

RCII may subsequently have been transformed into RCI by formation of the Fx cluster and eventually the capturing of a soluble 2[4Fe-4S] protein as an RC-associated subunit. These additions would have allowed electrons to leave the space of the membrane and serve for reductive processes in the dark reactions of photosynthesis. Our present knowledge concerning distribution of HiPIPs among species indicate that this electron carrier would have been invented only lately within the branch of the proteobacteria. Tbe evolutionary driving... 

Dong, Y., Zhu, H., Sagnella, G. A. etal. (1999). Association between the C825T polymorphism of the G protein beta3- subunit gene and hypertension in blacks. Hypertension, 34, 1193-6. 

Hengstenberg, C.,Schunkert, H., Mayer, B. etal. (2001). Association between a polymorphism in the G protein beta3 subunit gene (GNB3) with arterial hypertension but not with myocardial infarction. Cardiovasc. Res., 49 820-7. 

Kunugi, H., Kato, T., Fukuda, R. el al. (2002). Association study of C825T polymorphism of the G-protein beta3 subunit gene with schizophrenia and mood disorders. /. Neural Transm. 109, 213-18. 

Lin, C. N., Tsai, S. J. Hong, C. J. (2001a). Association analysis of a functional G protein beta3 subunit Gene polymorphism (C825T) in mood disorders. Neuropsychobiology, 44, 118-21. 

Siffert, W., Rosskopf, D., Siffert, G. etal. (1998). Association of a human G protein beta3 subunit variant with hypertension. Nat. Genet., 18, 45-8. 

Siffert, W., Forster, P., Jockel, K. H. etal. (1999). Worldwide ethnic distribution of the G protein beta3 subunit 825T allele and its association with obesity in Caucasian, Chinese, and Black African individuals. /. Am. Soc. Nephrol., 10, 1921-30. 

Lee, H.-J., Cha, J.-H., Ham, B.-J. etal. (2004). Association between a G-protein boldbeta3 subunit gene polymorphism and the symptomatology and treatment responses of major depressive disorders. Pharmacogenomics J., 4, 29-33. 

In addition to G protein a subunits, / subunits of G proteins also associate with 8 receptors and may be involved in 8 receptor signaling. Antisera directed against... 

G protein y subunits are modified on their C-terminal cysteine residues by isoprenylation [26,27]. There is now strong evidence that this modification plays a key role in anchoring the ysubunit and its associated P subunit to the plasmalemma. The importance of this anchoring is illustrated in Figure 19-2, which shows that the ability of py subunits to direct GRKs to ligand-bound receptors depends on this membrane localization. 

Rab is a family of small G proteins involved in membrane vesicle trafficking. Mammalian tissues contain around 30 forms of Rab, which specifically associate with the various types of membrane vesicles and organelles that exist in cells [30,31]. Rab proteins, named originally as ras-related proteins in brain, are isoprenylated and associate with membranes, as do isoprenylated Ras and G protein y subunits. However, unlike these other G proteins, the GTP and GDP binding to Rab appears to regulate its association with membrane compartments. 

This is not the only example. Recently, polymorphisms in the G protein p3-subunit gene have been shown to predict response to hydrochlorothiazide (Turner et al., 2001). Psaty et al. identified a subset of patients with a variant of the a-adducin gene that were associated with a lower risk of myocardial infarction and cerebral hemorrhage with diuretic therapy (Psaty et al., 2002). In addition, Genaissance has indicated that it has identified markers that predict the response to the statins, a class of drugs used to lower cholesterol. 

Matsunaga, T., Nagasumi, K., Yamamura, T., et al. (2005) Association of C825T polymorphism of G protein beta3 subunit with the autonomic nervous system in young healthy Japanese individuals. Am. J. Hypertens. 18, 523-529. 

Muller, D. J., De, L., V, Sicard, T., et al. (2005) Suggestive association between the C825T polymorphism of the G-protein beta3 subunit gene (GNB3) and clinical improvement with antipsychotics in schizophrenia. Eur. Neuropsychopharmacol. 15, 525-531. 

Figure 12.22 Dissociation/association of G-proteins associated with GTP/GDP exchange. The G-protein is trimeric when GDP is bound. Conversion of GDP to GTP allows the a-subunit to dissociate from trimer. The free a-subunit is now biochemically active and it migrates along the inner surface of the cell membrane to activate adenyl cyclase. Hydrolysis of GTP to GDP allows the subunits to re-associate and the a-subunit is now inactive (see Figures 12.6 and 12.15).

The G proteins with which G protein-coupled receptors interact are heterotrimeric complexes composed of a, P, and y subunits. In its inactive state, the G-protein a subunit is bound to GDP and associates with a Py dimer. Upon receptor activation, the a subunit opens its guanine nucleotide binding site and releases its bound GDP, allowing GTP, which is present in higher concentrations in the cell, to bind in its place. The GTP-bound a subunit has a lower affinity for the Py dimer and dissociates from it, freeing both the a sub-... 

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