The cAMP Signaling Pathway and Direct Protein Kinase A Phosphorylation Regulate Polycystin-2 (TRPP2) Channel Function

Cantero, María del Rocío; Velázquez, Irina Florencia; Streets, Andrew J.; Ong, Albert; Cantiello, Horacio F.

doi:10.1074/jbc.m115.661082

Cited by 22 publications

(9 citation statements)

References 67 publications

(30 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, TRPM4 exhibits activation as a result of G s stimulation in an Epac1-and IP 3 R-mediated Ca 2+ release-dependent manner (Mironov and Skorova, 2011), and TRPM7 can also be potentiated by PKA (Takezawa et al, 2004). Phosphorylation of TRPP1 by PKA also increases channel P o (Cantero del Rocío et al, 2015).…”

Section: G S -Mediated Reduction Of Trp Channel Activity Complements mentioning

confidence: 99%

The Ion Channel and GPCR Toolkit of Brain Capillary Pericytes

Hariharan

Weir

Robertson

et al. 2020

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Brain pericytes reside on the abluminal surface of capillaries, and their processes cover ~90% of the length of the capillary bed. These cells were first described almost 150 years ago (Eberth, 1871; Rouget, 1873) and have been the subject of intense experimental scrutiny in recent years, but their physiological roles remain uncertain and little is known of the complement of signaling elements that they employ to carry out their functions. In this review, we synthesize functional data with single-cell RNAseq screens to explore the ion channel and G protein-coupled receptor (GPCR) toolkit of mesh and thin-strand pericytes of the brain, with the aim of providing a framework for deeper explorations of the molecular mechanisms that govern pericyte physiology. We argue that their complement of channels and receptors ideally positions capillary pericytes to play a central role in adapting blood flow to meet the challenge of satisfying neuronal energy requirements from deep within the capillary bed, by enabling dynamic regulation of their membrane potential to influence the electrical output of the cell. In particular, we outline how genetic and functional evidence suggest an important role for Gs-coupled GPCRs and ATP-sensitive potassium (KATP) channels in this context. We put forth a predictive model for long-range hyperpolarizing electrical signaling from pericytes to upstream arterioles, and detail the TRP and Ca2+ channels and Gq, Gi/o, and G12/13 signaling processes that counterbalance this. We underscore critical questions that need to be addressed to further advance our understanding of the signaling topology of capillary pericytes, and how this contributes to their physiological roles and their dysfunction in disease.

show abstract

Section: G S -Mediated Reduction Of Trp Channel Activity Complements mentioning

confidence: 99%

The Ion Channel and GPCR Toolkit of Brain Capillary Pericytes

Hariharan

Weir

Robertson

et al. 2020

Front. Cell. Neurosci.

View full text Add to dashboard Cite

show abstract

“…, ; Cantero Mdel et al . ). Specifically, phosphorylation on Ser812 modifies the sensitivity of the PC2 channel and shifts the calcium‐dependent open probability curve so that the channel is more sensitive to calcium level changes (Cai et al .…”

Section: Introductionmentioning

confidence: 97%

Structural studies of the C‐terminal tail of polycystin‐2 (PC2) reveal insights into the mechanisms used for the functional regulation of PC2

Yang

Ehrlich

2016

The Journal of Physiology

View full text Add to dashboard Cite

Mutations in polycystin‐2 (PC2) lead to autosomal dominant polycystic kidney disease (ADPKD). The molecular mechanism linking mutations in PC2 and the pathogenesis of ADPKD is not well understood. Therefore, understanding the functional regulation of PC2 and its interaction with other proteins under both physiological and pathogenic conditions is important for elucidating the disease mechanism and identifying potential molecular targets for treatment. Normally, PC2 functions as a calcium‐permeable channel whose activity is regulated by calcium binding to the C‐terminal domain of PC2 (PC2 Cterm). The PC2 Cterm is also involved in the PC2 channel assembly and hetero‐oligomerization with other binding partners in cells. Different functional domains of the PC2 Cterm have been studied using structural approaches. Within the PC2 Cterm, there is a calcium‐binding EF‐hand domain, crucial for the calcium‐dependent activity of the PC2 channel. Downstream of the EF‐hand domain lies a coiled‐coil region, which is involved in the assembly and hetero‐interaction of the PC2 protein. The PC2 Cterm can form an oligomer, mediated by the coiled‐coil region. Although PC2 Cterm has been extensively studied for its relationship with ADPKD and its importance in PC2 regulation, there are misunderstandings with respect to the definition of the domain topology within the PC2 Cterm and the functional role of each domain. Here, we review previous studies that connect the molecular properties of the domains of PC2 Cterm to distinct aspects of PC2 functions and regulation.

show abstract

“…For instance, PC2 localization and channel activity are regulated by phosphorylation (7,41–43), IP 3 -induced Ca 2+ release (44), and membrane lipid composition and intracellular Ca 2+ (45–47). Each of these regulatory mechanisms involves second-messenger-dependent signaling that may be downstream of PC1-mediated G-protein signaling.…”

Section: Discussionmentioning

confidence: 99%

A mutation affecting polycystin-1 mediated heterotrimeric G-protein signaling causes PKD

Parnell

Magenheimer

Maser

et al. 2018

Human Molecular Genetics

View full text Add to dashboard Cite

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the growth of renal cysts that ultimately destroy kidney function. Mutations in the PKD1 and PKD2 genes cause ADPKD. Their protein products, polycystin-1 (PC1) and polycystin-2 (PC2) have been proposed to form a calcium-permeable receptor-channel complex; however the mechanisms by which they function are almost completely unknown. Most mutations in PKD1 are truncating loss-of-function mutations or affect protein biogenesis, trafficking or stability and reveal very little about the intrinsic biochemical properties or cellular functions of PC1. An ADPKD patient mutation (L4132Δ or ΔL), resulting in a single amino acid deletion in a putative G-protein binding region of the PC1 C-terminal cytosolic tail, was found to significantly decrease PC1-stimulated, G-protein-dependent signaling in transient transfection assays. Pkd1ΔL/ΔL mice were embryo-lethal suggesting that ΔL is a functionally null mutation. Kidney-specific Pkd1ΔL/cond mice were born but developed severe, postnatal cystic disease. PC1ΔL protein expression levels and maturation were comparable to those of wild type PC1, and PC1ΔL protein showed cell surface localization. Expression of PC1ΔL and PC2 complexes in transfected CHO cells failed to support PC2 channel activity, suggesting that the role of PC1 is to activate G-protein signaling to regulate the PC1/PC2 calcium channel.

show abstract

The cAMP Signaling Pathway and Direct Protein Kinase A Phosphorylation Regulate Polycystin-2 (TRPP2) Channel Function

Cited by 22 publications

References 67 publications

The Ion Channel and GPCR Toolkit of Brain Capillary Pericytes

The Ion Channel and GPCR Toolkit of Brain Capillary Pericytes

Structural studies of the C‐terminal tail of polycystin‐2 (PC2) reveal insights into the mechanisms used for the functional regulation of PC2

A mutation affecting polycystin-1 mediated heterotrimeric G-protein signaling causes PKD

Contact Info

Product

Resources

About