Different cAMP sources are critically involved in G protein–coupled receptor CRHR1 signaling

Abstract

G protein–coupled receptor CRHR1 activates both soluble adenylyl cyclase (sAC) and transmembrane adenylyl cyclases. Here, Inda et al. show that only sAC activity is essential for internalization-dependent cAMP and sustained ERK1/2 activation responses, revealing a functional association between sAC-generated cAMP and endosome-based G protein–coupled receptor signaling.

cAMP-dependent cell differentiation triggered by activated CRHR1 in hippocampal neuronal cells

“…CRH induced a strong phosphorylation of ERK1/2 at the early time point of 5 min and a small ERK1/2 response at 30 min and 3 h time points, consistent with the temporal profile of ERK1/2 activation in HT22-CRHR1 cells 13 . When serum was used as stimulus, ERK1/2 was also activated at the early time point (5 min) and modestly at 30 min and 3 h. It has been previously shown that a rise in cAMP leads to ERK1/2 activation in these cells 9 . Notably, the responses were additive when cells were stimulated with CRH and serum simultaneously, suggesting that CRH and serum activate ERK1/2 through different mechanisms.

Figure 6CRH- and serum-triggered responses in HT22-CRHR1 cells.

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“…Furthermore, we have demonstrated that sAC-generated cAMP is specifically involved in cAMP generation after CRHR1 internalization and required for the sustained “endocytic” phase of ERK1/2 signalling 9 . Here, we provide additional evidence of a functional diversification between tmACs and sAC.…”

“…Importantly, sAC, but not tmAC, is essential for endocytosis-dependent cAMP production 9 . We asked whether the endocytosis-dependent cAMP pool was critical for the CRH neuritogenic effect.…”

GPCR Signaling and Trafficking: The Long and Short of It

“…The functional consequences in some instances display biased responses, where the cell surface signal elicits one set of actions while the signal from internalized receptors exhibits an alternate effect. Emerging evidence demonstrates that signaling by some GPCRs including peptide hormone receptors PTHR [13], thyroid-stimulating receptor (TSHR) [14], glucagon-like peptide 1 receptor (GLP1R) [15], the pituitary adenylate cyclase activating polypeptide (PACAP) type 1 receptor [16], the vasopressin V2R receptor [17], corticotropin-releasing hormone receptor 1 (CRHR1) [18] and others (Table 1) is not restricted to cell membranes but exhibits ligand-biased persistent G protein signaling that depends on internalization of the GPCR bound to β-arrestins. Such β-arrestin-dependent sustained Gs interaction and cAMP signaling has been expanded to monoamine receptors including the β 2 adrenergic receptor (β 2 AR) [7], and dopamine D1R receptor [19].…”

“…Instead, TGR5 signals from plasma membrane lipid rafts that facilitate transactivation of EGFR and ERK1/2 stimulation. These findings imply that cAMP originating from different sources [18] and the spatiotemporal corralling of cAMP signaling [55] also condition the duration of receptor activity.…”