Pancreatic Islet Cells Express a Family of Inwardly Rectifying K+ Channel Subunits Which Interact to Form G-protein-activated Channels

Ferrer, Jorge; Nichols, Colin G.; Makhina, Elena; Salkoff, Lawrence; Bernstein, Josh; Gerhard, D. S.; Wasson, Jon; Ramanadham, Sasanka; Permutt, Alan

doi:10.1074/jbc.270.44.26086

Cited by 74 publications

(38 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Assuming equal amounts of wt and wv proteins and random assembly of subunits into tetrameric channels [11], these conditions will result in 15/16 of channels containing at least one wt subunit. Many members of the Kit 3.0 subfamily of Gprotein-sensitive inward rectifiers form heteromeric channels [12,13] and this may reflect the preferred situation [10]. Indeed, coexpression of all other members of the Kir 3.0 subfamily with wv resulted in reduced, G-131yz-insensitive wholecell currents and prolonged oocyte viability.…”

Section: Discussionmentioning

confidence: 99%

Heteromeric channel formation and Ca²⁺‐free media reduce the toxic effect of the weaver K_ir 3.2 allele

et al. 1996

View full text Add to dashboard Cite

weaver mice have a severe hypoplasia of the cerebellum with an almost complete loss of the midline granule cells. Recent genetic studies of weaver mice have identified a mutation resulting in an amino acid substitution (G156S) in the pore of the inwardly rectifying potassium channel subunit Kir 3.2. When expressed in Xenopus oocytes the weaver mutation alters channel selectivity from a potassium-selective to a nonspecific cation-selective pore. In this study we confirm by cell-attached patch-clamp recording that the mutation produces a non-selective cation channel. We also demonstrate that the cell death induced by weaver expression may be prevented by elimination of calcium from the extracellnlar solution as well as by coexpression with the wild-type Kir 3.2 allele, or other members of the Kir 3.0 subfamily. These results suggest that the weaver defect in Kir 3.2 may cause cerebellar cell death by cell swelling and calcium overload. Cells which express the weaver subunit, but which normally survive, may do so because of heteromeric subunit assembly with wild-type subunits of the Kir 3.0 subfamily.

show abstract

Section: Discussionmentioning

confidence: 99%

Heteromeric channel formation and Ca²⁺‐free media reduce the toxic effect of the weaver K_ir 3.2 allele

et al. 1996

View full text Add to dashboard Cite

show abstract

“…Human dopamine D3 and D2L receptors activate G-protein-coupled inward rectifier potassium channels (GIRKs) in mammalian cells (31) and, specifically, dopamine receptor 2 forms stable complexes with Kir3 channels (32). Several GIRK isoforms have been found in human pancreatic islets (33). Moreover, KCNJ9 (GIRK3, member of the GIRK family) is present in the pancreas and was proposed as a candidate gene for type II diabetes mellitus in the Pima Indian population (34).…”

Section: Discussionmentioning

confidence: 99%

Dopamine D2-like Receptors Are Expressed in Pancreatic Beta Cells and Mediate Inhibition of Insulin Secretion

Rubı́

Ljubicic

Pournourmohammadi

et al. 2005

Journal of Biological Chemistry

225

205

View full text Add to dashboard Cite

Dopamine is a neurotransmitter that plays a critical role in neurological and psychiatric disorders, such as schizophrenia, Parkinson disease, and drug addiction (1). Increasing evidence also shows implication of dopamine in various physiological functions such as cell proliferation (2), gastrointestinal protection (3), and inhibition of prolactin secretion (4). Effects of dopamine on insulin secretion in general and on pancreatic beta cell function in particular have been poorly studied. Insulin exocytosis from the beta cell is primarily controlled by metabolismsecretion coupling. First, glucose equilibrates across the plasma membrane and is phosphorylated by glucokinase, initiating glycolysis (5). Subsequently, mitochondrial metabolism generates ATP, which promotes the closure of ATP-sensitive potassium channels and, as a consequence, depolarization of the plasma membrane (6). This leads to calcium influx through voltage-gated calcium channels and a rise in cytosolic calcium, triggering insulin exocytosis (6, 7). Additional signals participating in the amplifying pathway (8) are necessary to reproduce the sustained secretion elicited by glucose. Insulin secretion evoked by glucose metabolism can be further modulated by parasympathetic and sympathetic neurotransmitters (9).Treatment with dopamine precursor L-dopa in humans suffering from Parkinson disease reduces insulin secretion upon oral glucose tolerance test (10). In rodents, a single injection with L-dopa results in the accumulation of dopamine in beta cells and inhibition of the insulin secretory responses (11,12). In isolated islets, analogues of dopamine inhibit glucose-stimulated insulin release (13), whereas one study reports potentiation of insulin secretion upon acute dopamine accumulation (14). Taken as a whole, these previous studies suggest that beta cells might be directly responsive to dopamine. Here, we investigated the molecular mechanisms implicated in beta cell responses to dopamine action. In particular, the present data demonstrate the presence of dopamine receptors in beta cells. Moreover, the inhibitory effects of dopamine are predominantly ascribed to activation of the D2-like receptor family members. MATERIALS AND METHODS INS-1E Cells and Pancreatic Islets-INS-1Ecells, used as a well differentiated beta cell clone (15), were cultured in a humidified atmosphere containing 5% CO 2 in a medium composed of RPMI 1640 supplemented with 10 mM Hepes, 5% (v/v) heat-inactivated fetal calf serum, 2 mM glutamine, 100 units/ml penicillin, 100 g/ml streptomycin, 1 mM sodium pyruvate, and 50 M 2-mercaptoethanol. For rodent islets, Wistar rats or BALB/c mice weighing 200 -250 g and 25-30 g, respectively, were obtained from in-house breeding (CMU-Zootechnie, Geneva, Switzerland). We followed the principles of laboratory animal care, and the study was approved by the responsible ethics committee. Pancreatic islets were isolated by collagenase digestion and handpicking from male Wistar rats or BALB/c mice as described previously (16). Isolated islets w...

show abstract

“…In the brain and heart, Kir3.1 forms functional K G channels by assembling with other Kir3.0 subunits such as GIRK2/Kir3.2, GIRK3/Kir3.3 (10,11), and GIRK4/CIR/Kir3.4 (12). Because Kir3.1 mRNA was detected in the anterior pituitary lobe (13) and pancreatic islet (14), this subunit may also contribute to the formation of K G channels in endocrine cells. The anterior pituitary lobe contains several kinds of endocrine cells: lactotrophs, somatotrophs, corticotrophs, and thyrotrophs.…”

mentioning

confidence: 99%

Secretagogue-induced Exocytosis Recruits G Protein-gated K+ Channels to Plasma Membrane in Endocrine Cells

Morishige

Inanobe²,

Yoshimoto³

et al. 1999

Journal of Biological Chemistry

View full text Add to dashboard Cite

Stimulation-regulated fusion of vesicles to the plasma membrane is an essential step for hormone secretion but may also serve for the recruitment of functional proteins to the plasma membrane. While studying the distribution of G protein-gated K ؉ (K G ) channels in the anterior pituitary lobe, we found K G channel subunits Kir3.1 and Kir3.4 localized on the membranes of intracellular dense core vesicles that contained thyrotropin. Stimulation of these thyrotroph cells with thyrotropinreleasing hormone provoked fusion of vesicles to the plasma membrane, increased expression of Kir3.1 and Kir3.4 subunits in the plasma membrane, and markedly enhanced K G currents stimulated by dopamine and somatostatin. These data indicate a novel mechanism for the rapid insertion of functional ion channels into the plasma membrane, which could form a new type of negative feedback control loop for hormone secretion in the endocrine system.The G protein-gated K ϩ (K G ) 1 channel, a member of the inwardly rectifying K ϩ (Kir) channel family, is directly activated by pertussis toxin-sensitive G proteins. This system was first discovered in the muscarinic deceleration of the heartbeat (1). More recently, it is considered to play an essential role in the hormone-mediated inhibitory regulation of neural excitability (1, 2). Electrophysiological studies have revealed that a variety of inhibitory receptors, including M 2 -muscarinic, A 1 -purinergic, D 2 -dopamine, ␣ 2 -adrenergic, serotonin, ␥-aminobutyric acid type B, opioid, and somatostatin receptors in the brain, are coupled to K G channels (3). In endocrine organs such as the anterior pituitary lobe and pancreatic islet, it was also reported that some neurotransmitters including dopamine and somatostatin hyperpolarize the membrane by activating K G channels, which results in the inhibition of hormone secretion (4 -7).The main subunit of K G channels has been cloned from the heart and designated GIRK1/Kir3.1 (8, 9). In the brain and heart, Kir3.1 forms functional K G channels by assembling with other Kir3.0 subunits such as GIRK2/Kir3.2, GIRK3/Kir3.3 (10, 11), and GIRK4/CIR/Kir3.4 (12). Because Kir3.1 mRNA was detected in the anterior pituitary lobe (13) and pancreatic islet (14), this subunit may also contribute to the formation of K G channels in endocrine cells. The anterior pituitary lobe contains several kinds of endocrine cells: lactotrophs, somatotrophs, corticotrophs, and thyrotrophs. Although electrophysiological experiments have shown that somatostatin or dopamine activate K G currents in lactotrophs (4) and also in several cell lines derived from the anterior pituitary lobe, such as GH3 (5) and AtT20 (6), the cellular and subcellular localizations of K G channels in in vivo pituitary endocrine cells have not been examined.In this study, using a polyclonal antibody specific to Kir3.1, we found that this subunit was expressed only in thyrotroph cells and, surprisingly, was localized predominantly on intracellular secretory vesicles. Kir3.4 was co-localized on the vesicles w...

show abstract

Pancreatic Islet Cells Express a Family of Inwardly Rectifying K+ Channel Subunits Which Interact to Form G-protein-activated Channels

Cited by 74 publications

References 30 publications

Heteromeric channel formation and Ca²⁺‐free media reduce the toxic effect of the weaver K_ir 3.2 allele

Heteromeric channel formation and Ca²⁺‐free media reduce the toxic effect of the weaver K_ir 3.2 allele

Dopamine D2-like Receptors Are Expressed in Pancreatic Beta Cells and Mediate Inhibition of Insulin Secretion

Secretagogue-induced Exocytosis Recruits G Protein-gated K+ Channels to Plasma Membrane in Endocrine Cells

Contact Info

Product

Resources

About

Pancreatic Islet Cells Express a Family of Inwardly Rectifying K+ Channel Subunits Which Interact to Form G-protein-activated Channels

Cited by 74 publications

References 30 publications

Heteromeric channel formation and Ca2+‐free media reduce the toxic effect of the weaver Kir 3.2 allele

Heteromeric channel formation and Ca2+‐free media reduce the toxic effect of the weaver Kir 3.2 allele

Dopamine D2-like Receptors Are Expressed in Pancreatic Beta Cells and Mediate Inhibition of Insulin Secretion

Secretagogue-induced Exocytosis Recruits G Protein-gated K+ Channels to Plasma Membrane in Endocrine Cells

Contact Info

Product

Resources

About

Heteromeric channel formation and Ca²⁺‐free media reduce the toxic effect of the weaver K_ir 3.2 allele

Heteromeric channel formation and Ca²⁺‐free media reduce the toxic effect of the weaver K_ir 3.2 allele