Disease relevance of Gem

• In cells expressing CB-1 ("A-2" cells), cannabinoid agonist potently and stereospecifically activated Kir via a pertussis toxin-sensitive G protein [1].
• To test whether interaction between Kir 1.1 and CFTR is required to mediate the renal effects of glibenclamide (15 mg/kg), clearance experiments were performed comparing wild type (WT) and Cftr(tm2cam) Delta F508 cystic fibrosis (CF) mice [2].
• Dysfunction of Kir channels in animal models can lead to severe phenotypes ranging from early postnatal death to an increased susceptibility to develop epileptic seizures [3].
• Physiological alterations, such as a strong downregulation of inwardly rectifying K+ (Kir) currents, were found after retinal detachment (man, rabbit) and after ischemia/reperfusion (rat) but not in more slowly progressing retinal degenerations (Borna Disease Virus-infected rats, RCS rats) [4].
• We describe the way in which the gating of Kir channel subunits plays an important role in polygenic CNS diseases, such as white matter disease, epilepsy and Parkinson's disease [3].

High impact information on Gem

• Regulation of Ca2+ channel expression at the cell surface by the small G-protein kir/Gem [5].
• Inhibition of L-type Ca2+ channels by kir/Gem prevents Ca2+-triggered exocytosis in hormone-secreting cells [5].
• Deregulated Gem expression prevented proliferation of normal and transformed 3T3 cells [6].
• These results suggest that Gem is a regulatory protein, possibly participating in receptor-mediated signal transduction at the plasma membrane [6].
• A gene encoding a 35-kilodalton guanosine triphosphate (GTP)-binding protein, Gem, was cloned from mitogen-induced human peripheral blood T cells [6].

Biological context of Gem

• Phosphorylation of critical serine residues in Gem separates cytoskeletal reorganization from down-regulation of calcium channel activity [7].
• Inward-rectifier potassium channels (Kir channels) stabilize the resting membrane potential and set a threshold for excitation in many types of cell [8].
• In summary, Kir2.1 gene expression in arterial smooth muscle is required for Kir currents and K(+)-induced dilations in cerebral arteries [9].
• In addition, the weaver phenotype, a neurological disorder in mice, has also been associated with mutations in a Kir channel subtype [10].
• Further genetic linkage analysis and full understanding of the consequence that a defect in a Kir channel would have on disease pathogenesis are among the priorities in this emerging field of molecular medicine [10].

Anatomical context of Gem

• The overexpression of wild-type Gem in pancreatic beta-cell line MIN6 cells suppressed Ca2+-triggered secretion, whereas overexpression of GemS88N induced Ca2+-triggered secretion to control level [11].
• RGK proteins are small Ras-related GTP-binding proteins that function as potent inhibitors of voltage-dependent calcium channels, and two members of the family, Gem and Rad, modulate Rho-dependent remodeling of the cytoskeleton [12].
• Kir currents were observed in cerebral artery myocytes isolated from control neonatal animals but were absent in myocytes from Kir2.1(-/-) animals [9].
• Of 11 members of the Kir channel family examined with reverse transcription-PCR, we could detect only expression of KAB-2 (Kir4.1) mRNA in stria vascularis [13].
• These experiments identify an inward rectifier K+ (Kir) channel expressed in mouse cortical and white matter astrocytes at the molecular level [14].

Associations of Gem with chemical compounds

• An endogenous cannabinoid, anandamide, activated Kir and inhibited ICa as efficaciously as potent cannabinoid agonist [1].
• Because EP was depressed by vascular perfusion of Ba2+, an inhibitor of inwardly rectifying K+ (Kir) channels, but not by either 4-aminopyridine or tetraethylammonium, we examined the expression of Kir channel subunits in cochlear stria vascularis, the tissue that is supposed to play the central role in the generation of positive EP [13].
• Phosphatidylinositol 4,5-bisphosphate (PIP2) modulation of ATP and pH sensitivity in Kir channels. A tale of an active and a silent PIP2 site in the N terminus [15].
• In rats, glibenclamide acts as a K(+)-sparing diuretic by a mechanism that involves blockade of Kir 1.1 channels in the distal nephron [2].
• Further investigation revealed that glial Kir channels are rapidly inhibited upon activation of AMPA-type glutamate receptors, most probably due a receptor-mediated influx of Na+, which plugs the channels from the intracellular side [16].

Other interactions of Gem

• These results suggest that GTPase activity of Gem is required for the binding of Gem to BID that regulates VDCC activity through interaction with AID [11].
• In addition to regulating cytoskeletal reorganization, phosphorylation of serine 289 in conjunction with serine 23 results in bidentate 14-3-3 binding, leading to increased Gem protein half-life [7].
• Phosphorylation of serines 261 and 289, located in the C-terminal extension, is required for Gem-mediated cytoskeletal reorganization, while GTP and possibly calmodulin binding are required for calcium channel inhibition [7].

Analytical, diagnostic and therapeutic context of Gem

• Titration of dansyl-CaM with the Kir/Gem peptide gave an affinity constant of 1 nM [17].
• Gel-shift analysis showed that the complex formation between CaM and the Kir/Gem peptide is strictly calcium-dependent [17].
• Sequence analysis of selected clones and a database search revealed that genes such as the gene for Gem GTPase and uncharacterized genes that resemble genes for myosin phosphatase and protein-tyrosine-phosphatase are involved in cell invasion [18].
• Immunoprecipitation experiments suggested that brain expressed at least two subsets of Kir channels, heteromeric Kir4.1/5.1 and homomeric Kir4 [19].
• The single-channel conductance of approximately 42 pS was not altered with inflammation. mRNA for both Kir 6.1 and 6.2 were detected by RT-PCR [20].

References