Effect of Elevated Intracellular cAMP Levels on Actomyosin Contraction in Bovine Trabecular Meshwork Cells

Ramachandran, Charanya; Patil, Rajkumar V.; Sharif, Najam A.; Srinivas, Sangly P.

doi:10.1167/iovs.10-6241

Cited by 25 publications

(21 citation statements)

References 58 publications

(59 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, myocilin, a mutation in which is linked to juvenile-and adult-onset primary open angle glaucoma (Stone et al, 1997), diminishes cell:matrix interactions in TM cells by inhibiting Rho GTPase activity, indicating a potential functional link between myocilin and Rho GTPase in regulation of cell adhesive interactions (Shen et al, 2008). Furthermore, forskolin and cAMP-induced TM cell relaxation is linked to inactivation of Rho GTPase signaling via phosphorylation of RhoA (Ramachandran et al, 2011b). These observations suggest that Rho GTPase plays a central role in TM biology by way of interacting with key regulatory molecular and cellular pathways.…”

Section: Role Of Rho/rho Kinase Signaling In the Conventional Ah Omentioning

confidence: 99%

Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research

Rao

Pattabiraman

Kopczynski

2017

Experimental Eye Research

133

166

View full text Add to dashboard Cite

Glaucoma is a leading cause of irreversible blindness worldwide. Elevated intraocular pressure (IOP) is considered to be a predominant risk factor for primary open angle glaucoma, the most prevalent form of glaucoma. Although the etiological mechanisms responsible for increased IOP are not completely clear, impairment in aqueous humor (AH) drainage through the conventional or trabecular pathway is recognized to be a primary cause in glaucoma patients. Importantly, lowering of IOP has been demonstrated to reduce progression of vision loss and is a mainstay of treatment for all types of glaucoma. Currently however, there are limited therapeutic options available for lowering IOP especially as it relates to enhancement of AH outflow through the trabecular pathway. Towards addressing this challenge, bench and bedside research conducted over the course of the last decade and a half has identified the significance of inhibiting Rho kinase for lowering IOP. Rho kinase is a downstream effector of Rho GTPase signaling that regulates actomyosin dynamics in numerous cell types. Studies from several laboratories have demonstrated that inhibition of Rho kinase lowers IOP via relaxation of the trabecular meshwork which enhances AH outflow. By contrast, activation of Rho GTPase/Rho kinase signaling in the trabecular outflow pathway increases IOP by altering the contractile, cell adhesive and permeability barrier characteristics of the trabecular meshwork and Schlemm’s canal tissues, and by influencing extracellular matrix production and fibrotic activity. This article, written in honor of the late David Epstein, MD, summarizes findings from both basic and clinical studies that have been instrumental for recognition of the importance of the Rho/Rho kinase signaling pathway in regulation of AH outflow, and in the development of Rho kinase inhibitors as promising IOP- lowering agents for glaucoma treatment.

show abstract

Section: Role Of Rho/rho Kinase Signaling In the Conventional Ah Omentioning

confidence: 99%

Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research

Rao

Pattabiraman

Kopczynski

2017

Experimental Eye Research

133

166

View full text Add to dashboard Cite

show abstract

“…31 It is known that there is a high level of cAMP in the aqueous humor although its origin is currently unknown. [32][33][34][35] If cAMP in the aqueous humor is the signal, then it most likely is converted to adenosine by phosphodiesterases. A role for adenosine in regulation of outflow resistance has been well documented.…”

Section: A Model For Regulation Of Outflow Facility By the Cb And Futmentioning

confidence: 99%

Control of Outflow Resistance by Soluble Adenylyl Cyclase

Lee

Marmorstein

2014

Journal of Ocular Pharmacology and Therapeutics

View full text Add to dashboard Cite

Glaucoma is a leading cause of blindness in the United States affecting as many as 2.2 million Americans. All current glaucoma treatment strategies aim to reduce intraocular pressure, even in patients with normal tension glaucoma. Typically, this is accomplished by reducing the rate of aqueous flow by limiting aqueous production or enhancing drainage using drugs and surgery. Whereas these strategies are effective in diminishing vision loss, some patients continue to lose vision and many discontinue use of their medications because of undesirable side effects. Drugs known to be effective in altering conventional outflow have for the most part been abandoned from modern clinical practice due to undesirable side effects. Identification of new drugs that could enhance conventional outflow, would offer additional options in the treatment of glaucoma and ocular hypertension. To this end, our laboratory has recently uncovered a novel pathway for regulation of conventional outflow by the ciliary body. This pathway is dependent on soluble adenylyl cyclase, an enzyme that catalyzes the generation of cyclic adenosine 3¢,5¢ monophosphate (cAMP) in response to bicarbonate.

show abstract

“…The extent of MLC phosphorylation is determined by two opposing pathways: MLCK (MLC Kinase)-driven phosphorylation and MLCP (MLC Phosphatase)-driven dephosphorylation (summarized in Fig. 2) (Somlyo and Somlyo, 2003; Srinivas, 2010; Ramachandran et al, 2011). MLCK is the dedicated kinase for phosphorylating MLC and is activated when bound to the Ca 2+ -calmodulin complex.…”

Section: Regulation Of the Barrier Integrity By Cortical Actin Cytoskmentioning

confidence: 99%

“…PKC (Protein Kinase C) inactivates MLCP through phosphorylation of CPI-17 (PKC-activated 17 kDa inhibitor protein of type 1 phosphatase;17 kDa), which is known to inactivate PP1Cδ (not shown in Fig. 2) (Somlyo and Somlyo, 2003; Srinivas, 2010; Ramachandran et al, 2011). Overall, the activation of Rho kinase and/or PKC results in actomyosin contraction.…”

Section: Regulation Of the Barrier Integrity By Cortical Actin Cytoskmentioning

confidence: 99%

“…In contrast to Rho kinase and PKC, Protein kinase A (PKA) opposes actomyosin contraction. Specifically, RhoA is phosphorylated by (PKA) at Ser-188 and this prevents dissociation of RhoA-GDI (RhoA-GDP-dissociation inhibitor) from RhoA-GDP and thereby curtails activation of RhoA (Ramachandran et al, 2011). …”

Section: Regulation Of the Barrier Integrity By Cortical Actin Cytoskmentioning

confidence: 99%

See 1 more Smart Citation

Cell signaling in regulation of the barrier integrity of the corneal endothelium

Srinivas

2012

Experimental Eye Research

Self Cite

View full text Add to dashboard Cite

The barrier integrity of the corneal endothelium, which is conferred by its tight and adherens junctions, is critical for the maintenance of deturgescence of the corneal stroma. Although characteristically leaky, the barrier integrity restricts fluid leakage into the stroma such that the rate of leak does not exceed the rate of the endothelial active fluid transport directed toward the aqueous humor. At a molecular level, the barrier integrity is influenced by the actin cytoskeleton and microtubules, which are coupled to tight and adherens junctions via a variety of linker proteins. Since the cytoskeleton is affected by Rho family small GTPases and p38 MAP kinase, among others, many pathophysiological stimuli induce plasticity to the cytoskeleton and thereby elicit dynamic regulation of the barrier integrity. This review presents an overview of the impact of several bioactive factors on the barrier integrity of the corneal endothelium through altered actin cytoskeleton and/or disassembly of microtubules. The main focus is on the effect of TNF-α (tumor necrosis factor-α) which is a pro-inflammatory molecule found in the intraocular milieu during allograft rejection and anterior uveitis. This cytokine elicits acute activation of p38 MAP kinase, induces disassembly of microtubules, disrupts the peri-junctional actomyosin ring, and concomitantly breaks down the barrier integrity. These effects of TNF-α could be inhibited by stabilizing the microtubules, co-treating with a selective p38 MAP kinase inhibitor, and elevating intracellular cAMP via A2B receptors or direct exposure to forskolin. Overall, the corneal edema following a potential breakdown of the endothelial barrier integrity can be rescued pharmacologically by inhibiting specific cell-signaling mechanisms.

show abstract

Effect of Elevated Intracellular cAMP Levels on Actomyosin Contraction in Bovine Trabecular Meshwork Cells

Cited by 25 publications

References 58 publications

Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research

Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research

Control of Outflow Resistance by Soluble Adenylyl Cyclase

Cell signaling in regulation of the barrier integrity of the corneal endothelium

Contact Info

Product

Resources

About