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Articles by L Birnbaumer
Total Records ( 5 ) for L Birnbaumer
  M Seth , Z. S Zhang , L Mao , V Graham , J Burch , J Stiber , L Tsiokas , M Winn , J Abramowitz , H. A Rockman , L Birnbaumer and P. Rosenberg
 

Rationale: Cardiac muscle adapts to increase workload by altering cardiomyocyte size and function resulting in cardiac hypertrophy. G protein–coupled receptor signaling is known to govern the hypertrophic response through the regulation of ion channel activity and downstream signaling in failing cardiomyocytes.

Objective: Transient receptor potential canonical (TRPC) channels are G protein–coupled receptor operated channels previously implicated in cardiac hypertrophy. Our objective of this study is to better understand how TRPC channels influence cardiomyocyte calcium signaling.

Methods and Results: Here, we used whole cell patch clamp of adult cardiomyocytes to show upregulation of a nonselective cation current reminiscent of TRPC channels subjected to pressure overload. This TRPC current corresponds to the increased TRPC channel expression noted in hearts of mice subjected to pressure overload. Importantly, we show that mice lacking TRPC1 channels are missing this putative TRPC current. Moreover, Trpc1/ mice fail to manifest evidence of maladaptive cardiac hypertrophy and maintain preserved cardiac function when subjected to hemodynamic stress and neurohormonal excess. In addition, we provide a mechanistic basis for the protection conferred to Trpc1/ mice as mechanosensitive signaling through calcineurin/NFAT, mTOR and Akt is altered in Trpc1/ mice.

Conclusions: From these studies, we suggest that TRPC1 channels are critical for the adaptation to biomechanical stress and TRPC dysregulation leads to maladaptive cardiac hypertrophy and failure.

  Z Zuberi , M Nobles , S Sebastian , A Dyson , S. Y Lim , R Breckenridge , L Birnbaumer and A. Tinker
  Background—

We explored the role that inhibitory heterotrimeric G-proteins play in ventricular arrhythmia.

Methods and Results—

Mice with global genetic deletion of Gi2 [Gi2 (–/–)] were studied and found, based on telemetry, to have a prolonged QT interval on surface ECG when awake. In vivo electrophysiology studies revealed that the Gi2 (–/–) mice have a reduced ventricular effective refractory period and a predisposition to ventricular tachycardia when challenged with programmed electrical stimulation. Neither control nor combined global deletion of Gi1 and Gi3 mice showed these abnormalities. There was no evidence for structural heart disease at this time point in the Gi2 (–/–) mice as assessed by cardiac histology and echocardiography. The absence of Gi2 thus leads to a primary electrical abnormality, and we explored the basis for this finding. With patch clamping, single isolated ventricular cells showed that Gi2 (–/–) mice had a prolonged ventricular action potential duration (APD) but steeper action potential shortening as the diastolic interval was reduced in restitution studies. Gene expression studies showed increased expression of L-type Ca2+ channel subunits, and patch clamping revealed an increase in these currents in Gi2 (–/–) mice. There were no changes in K+ currents.

Conclusions—

The absence of inhibitory G-protein signaling mediated through Gi2 is a substrate for ventricular arrhythmias.

  Y Li , L Birnbaumer and C. T. Teng
 

In selected tissues and cell lines, 17β-estradiol (E2) regulates the expression of estrogen-related receptor (ERR), a member of the orphan nuclear receptor family. This effect is thought to be mediated by the estrogen receptor (ER). However in the ER- and ERβ-negative SKBR3 breast cancer cell line, physiological levels of E2 also stimulate ERR expression. Here, we explored the molecular mechanism that mediates estrogen action in ER-negative breast cancer cells. We observed that E2, the ER agonist, as well as the ER antagonists ICI 182,780 and tamoxifen (TAM), a selective ER modulator, stimulate the transcriptional activity of the ERR gene and increase the production of ERR protein in SKBR3 cells. Moreover, the ERR downstream target genes expression and cellular proliferation are also increased. We show further that the G protein-coupled receptor GPR30/GPER-1 (GPER-1) mediates these effects. The GPER-1 specific ligand G-1 mimics the actions of E2, ICI 182,780, and TAM on ERR expression, and changing the levels of GPER-1 mRNA by overexpression or small interfering RNA knockdown affected the expression of ERR accordingly. Utilizing inhibitors, we delineate a different downstream pathway for ER agonist and ER antagonist-triggered signaling through GPER-1. We also find differential histone acetylation and transcription factor recruitment at distinct nucleosomes of the ERR promoter, depending on whether the cells are activated with E2 or with ER antagonists. These findings provide insight into the molecular mechanisms of GPER-1/ERR-mediated signaling and may be relevant to what happens in breast cancer cells escaping inhibitory control by TAM.

  N Zanou , G Shapovalov , M Louis , N Tajeddine , C Gallo , M Van Schoor , I Anguish , M. L Cao , O Schakman , A Dietrich , J Lebacq , U Ruegg , E Roulet , L Birnbaumer and P. Gailly
 

Skeletal muscle contraction is reputed not to depend on extracellular Ca2+. Indeed, stricto sensu, excitation-contraction coupling does not necessitate entry of Ca2+. However, we previously observed that, during sustained activity (repeated contractions), entry of Ca2+ is needed to maintain force production. In the present study, we evaluated the possible involvement of the canonical transient receptor potential (TRPC)1 ion channel in this entry of Ca2+ and investigated its possible role in muscle function. Patch-clamp experiments reveal the presence of a small-conductance channel (13 pS) that is completely lost in adult fibers from TRPC1–/– mice. The influx of Ca2+ through TRPC1 channels represents a minor part of the entry of Ca2+ into muscle fibers at rest, and the activity of the channel is not store dependent. The lack of TRPC1 does not affect intracellular Ca2+ concentration ([Ca2+]i) transients reached during a single isometric contraction. However, the involvement of TRPC1-related Ca2+ entry is clearly emphasized in muscle fatigue. Indeed, muscles from TRPC1–/– mice stimulated repeatedly progressively display lower [Ca2+]i transients than those observed in TRPC1+/+ fibers, and they also present an accentuated progressive loss of force. Interestingly, muscles from TRPC1–/– mice display a smaller fiber cross-sectional area, generate less force per cross-sectional area, and contain less myofibrillar proteins than their controls. They do not present other signs of myopathy. In agreement with in vitro experiments, TRPC1–/– mice present an important decrease of endurance of physical activity. We conclude that TRPC1 ion channels modulate the entry of Ca2+ during repeated contractions and help muscles to maintain their force during sustained repeated contractions.

  H Okawa , J Pahlberg , F Rieke , L Birnbaumer and A. P. Sampath
 

The high sensitivity of scotopic vision depends on the efficient retinal processing of single photon responses generated by individual rod photoreceptors. At the first synapse in the mammalian retina, rod outputs are pooled by a rod "ON" bipolar cell, which uses a G-protein signaling cascade to enhance the fidelity of the single photon response under conditions where few rods absorb light. Here we show in mouse rod bipolar cells that both splice variants of the Go subunit, Go1 and Go2, mediate light responses under the control of mGluR6 receptors, and their coordinated action is critical for maximizing sensitivity. We found that the light response of rod bipolar cells was primarily mediated by Go1, but the loss of Go2 caused a reduction in the light sensitivity. This reduced sensitivity was not attributable to the reduction in the total number of Go subunits, or the altered balance of expression levels between the two splice variants. These results indicate that Go1 and Go2 both mediate a depolarizing light response in rod bipolar cells without occluding each other’s actions, suggesting they might act independently on a common effector. Thus, Go2 plays a role in improving the sensitivity of rod bipolar cells through its action with Go1. The coordinated action of two splice variants of a single G may represent a novel mechanism for the fine control of G-protein activity.

 
 
 
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