Human G Protein γ11 and γ14 Subtypes Define a New Functional Subclass

Balcueva, Eric A.; Wang, Qin; Hughes, Heather; Kunsch, Charles; Yu, Zihui; Robishaw, Janet D.

doi:10.1006/excr.2000.4893

Cited by 34 publications

(31 citation statements)

References 42 publications

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“…Most nonretinal ␥ isoforms have a geranylgeranyl modification that partitions into membranes about 1-2 orders of magnitude more strongly than farnesyl (53). Several nonretinal ␥ isoforms, however, have been shown to be farnesylated, and two of these (␥ 11 and ␥ 14 ) form heterodimers with ␤ 1 (54,55), the ␤ isoform found in transducin ␤␥ and examined here. Both farnesylated ␤ 1 ␥ 11 and a geranylgeranylated mutant activate adenylyl cyclase II equally well in an in vivo assay (54) indicating that there are factors in addition to farnesylation (e.g.…”

Section: Discussionmentioning

confidence: 77%

“…Several nonretinal ␥ isoforms, however, have been shown to be farnesylated, and two of these (␥ 11 and ␥ 14 ) form heterodimers with ␤ 1 (54,55), the ␤ isoform found in transducin ␤␥ and examined here. Both farnesylated ␤ 1 ␥ 11 and a geranylgeranylated mutant activate adenylyl cyclase II equally well in an in vivo assay (54) indicating that there are factors in addition to farnesylation (e.g. electrostatics or protein-protein interactions) that drive membrane binding.…”

Section: Discussionmentioning

confidence: 80%

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The Role of Electrostatic Interactions in the Regulation of the Membrane Association of G Protein βγ Heterodimers

Murray¹,

McLaughlin²,

Honig³

2001

Journal of Biological Chemistry

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In this paper we report calculations of electrostatic interactions between the transducin (G t ) ␤␥ heterodimer (G t ␤␥) and phospholipid membranes. Although membrane association of G t ␤␥ is due primarily to the hydrophobic penetration into the membrane interior of a farnesyl chain attached to the ␥ subunit, structural studies have revealed that there is a prominent patch of basic residues on the surface of the ␤ subunit surrounding the site of farnesylation that is exposed upon dissociation from the G t ␣ subunit. Moreover, phosducin, which produces dissociation of G t ␤␥ from membranes, interacts directly with G t ␤␥ and introduces a cluster of acidic residues into this region. The calculations, which are based on the finite difference Poisson-Boltzmann method, account for a number of experimental observations and suggest that charged residues play a role in mediating protein-membrane interactions. Specifically, the calculations predict the following. 1) Favorable electrostatic interactions enhance the membrane partitioning due to the farnesyl group by an order of magnitude although G t ␤␥ has a large net negative charge (؊12). 2) This electrostatic attraction positions G t ␤␥ so that residues implicated in mediating the interaction of G t ␤␥ with its membrane-bound effectors are close to the membrane surface.3) The binding of phosducin to G t ␤␥ diminishes the membrane partitioning of G t ␤␥ by an order of magnitude. 4) Lowering the ionic strength of the solution converts the electrostatic attraction into a repulsion. Sequence analysis and homology model building suggest that our conclusions may be generalized to other G␤␥ and phosducin isoforms as well.The interaction of proteins with cellular membranes is a central feature of signal transduction. Many proteins involved in interfacial signaling contain a lipophilic modification (e.g. myristate and farnesyl) that contributes to membrane association by partitioning hydrophobically into the membrane interior (1, 2). Examples of such proteins include heterotrimeric G proteins, small GTPases, and nonreceptor tyrosine kinases. A lipid modification alone usually cannot provide enough energy to keep a protein anchored to a cellular membrane (3) and often occurs in conjunction with additional membrane binding motifs. For example, most Src family kinases (1), H-and N-Ras (4), and many G␣ subunits (5) have dual lipophilic modifications, while other proteins, e.g. K-Ras4B (6, 7) and Src itself (8, 9), have both a lipophilic attachment and an adjacent cluster of basic residues that are attracted electrostatically to the charged surface of lipid bilayers. Heterotrimeric G proteins are acylated on the ␣ subunit and prenylated on the ␥ subunit, and the membrane association of the inactive heterotrimer is due primarily to the penetration of both of these lipophilic modifications into the hydrocarbon region of the membrane (10). The exchange of GTP for GDP on the ␣ subunit, catalyzed by an activated G protein-coupled receptor, results in the dissociation of G␣ from the G␤␥ h...

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 80%

The Role of Electrostatic Interactions in the Regulation of the Membrane Association of G Protein βγ Heterodimers

Murray¹,

McLaughlin²,

Honig³

2001

Journal of Biological Chemistry

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“…Potential cardiovascular interactions α 1 -Adrenergic activation in the heart induces a positive inotropic effect, likely due to increases in IP 3 . In human failing hearts the positive inotropic response of α 1 -AR activation may have greater physiological importance due to a decrease in the β-adrenergic effect.…”

Section: Potential Adverse Effectsmentioning

confidence: 99%

COMBINED USE OF Α-Adrenergic AND MUSCARINIC ANTAGONISTS FOR THE TREATMENT OF VOIDING DYSFUNCTION

2005

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Purpose-We provide an overview of the medical literature supporting the combined use of muscarinic and α-adrenergic antagonist therapy for the treatment of voiding dysfunction. The MEDLINE database (1966 of the United States National Library of Medicine was searched for pertinent studies. Materials and Methods-Results-Although the mechanism of action of α-adrenergic antagonist therapy for voiding dysfunction has traditionally been assumed to be relaxation of the periurethral, prostatic and bladder neck smooth muscle, substantial evidence supports action at extraprostatic sites involved in micturition, including the bladder dome smooth muscle, peripheral ganglia, spinal cord and brain. Likewise the mechanism of action of anticholinergic therapy has been traditionally assumed to be inhibition of the M 3 muscarinic receptor subtypes that mediate normal bladder contractions. However, M 2 receptor mediates hypertrophied bladder contractions and there is evidence for an M 2 component to the suprasacral control of voiding.Conclusions-Based on the physiology of α-adrenergic and muscarinic receptors the inhibition of each one would be expected to be more beneficial than that of either alone because they would work on 2 components of detrusor function. Patients who would likely benefit from this combination therapy are men with lower urinary tract symptoms, women with urgency/frequency syndrome (overactive bladder), patients with uninhibited bladder contractions due to neurogenic bladder, and patients with pelvic pain and voiding symptoms, ie interstitial cystitis and chronic prostatitis/chronic pelvic pain syndrome. Keywordsbladder; prostate; adrenergic alpha-antagonists; muscarinic antagonists; urination disorders The wide range of patients who might benefit from this type of treatment combination is considered to be large, perhaps several times the estimated 17 million patients in the United States with overactive bladder. 1 A patent application has been filed for the treatment of lower urinary tract (LUT) symptoms (LUTS) in men with benign prostatic hyperplasia (BPH) with this combination. 2

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“…For example, Gbg-dimers with the shorter farnesyl group are less able than those with a geranylgeranyl group to stimulate type II adenylyl cyclase and phospholipaseGb (Myung et al, 1999). Consequently, Gg 1 , Gg 11 , and Gg 14 form a functional subclass that is likely to have distinct interactions with membranes, receptors and e ectors; while expression of Gg 1 is restricted to the retina and brain, Gg 11 and Gg 14 are more widely distributed (Balcueva et al, 2000).…”

Section: Post-translational Modi®cationsmentioning

confidence: 99%