Activation of Phospholipase C-β1 via Gαq/11during Calcium Mobilization by Calcitonin Gene-related Peptide

Lee

Journal of Biological Chemistry

et al. 2005

The intracellular mechanisms of ischemic preconditioning (PC) in preventing lung dysfunction following transplantation, shock, and trauma remain poorly understood. Previously, we have shown that alveolar epithelial cells secrete calcitonin gene-related peptide (CGRP) under inflammatory stress. Using a hypoxia/ reoxygenation (H/R) and PC model, we found that CGRP was also secreted from human type II alveolar epithelial cells (

Section: Discussionmentioning

confidence: 99%

Endogenous Calcitonin Gene-related Peptide Protects Human Alveolar Epithelial Cells through Protein Kinase Cϵ and Heat Shock Protein

Lee

Journal of Biological Chemistry

et al. 2005

Journal of Biological Chemistry

“…Both PKC and calcium signaling are activated via the phospholipase C pathway. Activation of phospholipase C would be consistent with coupling to G␣ q as this G protein can activate PLC␤1 and ␤3 (26). However, activation can also be G␣ q -independent as G␤␥ can activate PLC␤2 (27).…”

mentioning

confidence: 87%

Involvement of Both Gq/11 and Gs Proteins in Gonadotropin-releasing Hormone Receptor-mediated Signaling in LβT2 Cells

Liu¹,

Usui²,

Evans³

et al. 2002

173

125

The hypothalamic hormone gonadotropin-releasing hormone (GnRH) stimulates the synthesis and release of the pituitary gonadotropins. GnRH acts through a plasma membrane receptor that is a member of the G protein-coupled receptor (GPCR) family. These receptors interact with heterotrimeric G proteins to initiate downstream signaling. In this study, we have investigated which G proteins are involved in GnRH receptormediated signaling in L␤T2 pituitary gonadotrope cells. We have shown previously that GnRH activates ERK and induces the c-fos and LH␤ genes in these cells. Signaling via the G i subfamily of G proteins was excluded, as neither ERK activation nor c-Fos and LH␤ induction was impaired by treatment with pertussis toxin or a cell-permeable peptide that sequesters G␤␥-subunits. GnRH signaling was partially mimicked by adenoviral expression of a constitutively active mutant of G␣ q (Q209L) and was blocked by a cell-permeable peptide that uncouples G␣ q from GPCRs. Furthermore, chronic activation of G␣ q signaling induced a state of GnRH resistance. A cell-permeable peptide that uncouples G␣ s from receptors was also able to inhibit ERK, c-Fos, and LH␤, indicating that both G q/11 and G s proteins are involved in signaling. Consistent with this, GnRH caused GTP loading on G s and G q/11 and increased intracellular cAMP. Artificial elevation of cAMP with forskolin activated ERK and caused a partial induction of c-Fos. Finally, treatment of G␣ q (Q209L)-infected cells with forskolin enhanced the induction of c-Fos showing that the two pathways are independent and additive. Taken together, these results indicate that the GnRH receptor activates both G q and G s signaling to regulate gene expression in L␤T2 cells.The family of G protein-coupled receptors is the largest and most complex group of integral membrane proteins involved in signal transduction. These receptors can be activated by a diverse array of external stimuli, including growth factors, neurotransmitters, peptide, and protein hormones, chemokines, and other ligands. Agonist binding to a specific receptor on the cell surface causes a conformational change in the receptor that allows it to interact with its cognate G protein, stimulating guanine nucleotide exchange on the ␣-subunit of the G protein. The release of the GTP-bound ␣-subunit and ␤␥-subunits from the receptor-G protein complex initiates a broad range of intracellular signaling events, including the activation of classical effectors such as phospholipase C, adenylate cyclases, and ion channels, and regulation of the intracellular level of inositol phosphates, calcium, cyclic AMP, and other second messengers (for reviews see Refs. 1-8).Gonadotropin-releasing hormone (GnRH) 1 is a hypothalamic decapeptide, which serves as a key regulator of the reproductive system. In the pituitary, GnRH signals are transmitted via a specific cell surface receptor, which is a member of the G protein-coupled receptor superfamily. When GnRH binds to its receptor, it induces interaction of the receptor with heterot...

“…These data indicate that CGRP-induced increases in ipsilateral ARNA and contralateral renal excretion function depend on the activation of TRPV1. It has been shown that CGRP receptor activation activates phospholipase C (PLC), which involves the G␣ q /11 subunit of G-proteins (Drissi et al, 1998). CAP can also activate PLC in TRPV1-positive cells, and the activation of phosphoinositides leads to TRPV1 activation (Lukacs et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Interdependent Regulation of Afferent Renal Nerve Activity and Renal Function: Role of Transient Receptor Potential Vanilloid Type 1, Neurokinin 1, and Calcitonin Gene-Related Peptide Receptors

Xie

Sachs

Wang³

2008

J Pharmacol Exp Ther

Our previous studies have shown that the activation of the transient receptor potential vanilloid type 1 (TRPV1) expressed in the renal pelvis leads to an increase in ipsilateral afferent renal nerve activity (ARNA) and contralateral renal excretory function, but the molecular mechanisms of TRPV1 action are largely unknown. This study tests the hypothesis that activation of receptors of neurokinin 1 (NK1) or calcitonin gene-related peptide (CGRP) by endogenously released substance P (SP) or CGRP following TRPV1 activation, respectively, governs TRPV1-induced increases in ARNA and renal excretory function. Capsaicin (CAP; 0.04, 0.4, and 4 nM), a selective TRPV1 agonist, administered into the renal pelvis dose-dependently increased ARNA. CAP (4 nM)-induced increases in ipsilateral ARNA or contralateral urine flow rate (Uflow) and urinary sodium excretion (UNa) were abolished by capsazepine (CAPZ), a selective TRPV1 antagonist, or 2-[1-imino-2-(2-antagonists, but not by CGRP8-37, a selective CGRP receptor antagonist. Both SP (7.4 nM) and CGRP (0.13 M) increased ARNA, Uflow, or UNa, and increases in these parameters induced by CGRP but not SP were abolished by CAPZ. CAP at 4 nM perfused into the renal pelvis caused the release of SP and CGRP, which was blocked by CAPZ but not by RP67580, L703,606, or CGRP8-37. Immunofluorescence results showed that NK1 receptors were expressed in sensory neurons in dorsal root ganglion and sensory nerve fibers innervating the renal pelvis. Taken together, our data indicate that NK1 activation induced by SP release upon TRPV1 activation governs TRPV1 function and that a TRPV1-dependent mechanism is operant in CGRP action.The transient receptor potential vanilloid type 1 (TRPV1) channel is a nonselective cation channel that can be activated by capsaicin (CAP), noxious heat, lipid metabolites, and protons (Guo et al., 1999;Julius and Basbaum, 2001;Klionsky et al., 2006). Our previous data show that activation of TRPV1 by CAP perfused into the unilateral renal pelvis leads to bilateral diuresis and natriuresis via a dual renorenal reflex and that this effect is abolished after ipsilateral renal denervation (Zhu et al., 2005). Moreover, hypertonic saline perfused into the renal pelvis causes increases in ipsilateral afferent renal nerve activity (ARNA) and contralateral renal excretory function by activation of TRPV1 and neurokinin 1 (NK1) receptors (Zhu et al., 2007). These data indicate that TRPV1-positive sensory nerves innervating the renal pelvis play an important role in regulating ARNA and maintaining sodium and water homeostasis, but the mechanism by whichTRPV1 activation induces elevated ARNA is largely unknown.Activation of TRPV1 expressed in sensory nerves of unmyelinated C-fibers or thinly myelinated A␦-fibers causes release of a variety of sensory neuropeptides, including substance P (SP) and calcitonin gene-related peptide (CGRP). SP and CGRP are colocalized in renal pelvis sensory nerves and may be totally depleted after CAP treatment (Hua et al., 1987). CGRP perfu...