Inflammatory response is important for our protection against infections and injuries, whereas uncontrolled inflammatory response could become destructive. Recent studies suggested that G protein signaling is involved in regulating different components of the inflammatory pathway. G protein-coupled receptors, for example formyl-peptide receptor like 1 (FPRL-1), somatostatin type 2 receptor (SSTR2) and α₂-adrenergic receptor have been shown to couple with Gα_i and Gα_q family proteins (in particular Gα₁₄) and lead to activation of downstream effectors such as NFκB and STAT3. Gα₁₄ is expressed in many immune cells. However, their function in inflammation and immune responses as well as the signaling mechanism of such function remain to be identified. In my current study, I found that activa...[ Read more ]

Inflammatory response is important for our protection against infections and injuries, whereas uncontrolled inflammatory response could become destructive. Recent studies suggested that G protein signaling is involved in regulating different components of the inflammatory pathway. G protein-coupled receptors, for example formyl-peptide receptor like 1 (FPRL-1), somatostatin type 2 receptor (SSTR2) and α₂-adrenergic receptor have been shown to couple with Gα_i and Gα_q family proteins (in particular Gα₁₄) and lead to activation of downstream effectors such as NFκB and STAT3. Gα₁₄ is expressed in many immune cells. However, their function in inflammation and immune responses as well as the signaling mechanism of such function remain to be identified. In my current study, I found that activation of FPRL-1 by WKYMVM in U87 astrocytoma cells leads to Ca²⁺ mobilization via Gα_i proteins and store-operated channels. On the other hand, activation of FPRL-1 in THP-1 monocytic cells leads to STAT3 and IKK phosphorylation via Gα₁₄/Gα₁₆. I also found that Gα₁₄ mediates NFκB and STAT3 activation via interaction with TPR1 and subsequent activation of the Ras/ERK signaling pathway. Disruption of the Gα₁₄/TPR1 interaction by either overexpression of the dominant negative mutant of TPR1 (TPR1ΔC) or siRNA targeting TPR1 significantly reduced Gα₁₄-induced Ras activation, as well as ERK, IKK and STAT3 Serine⁷²⁷ phosphorylation. Moreover, using a series of Gα₁₄/Gα_z chimeras, I have shown that Gα₁₄ may utilize structural regions different from Gα₁₆ and Gα_q for PLCβ and TPR1-interaction. My results suggested that the N-terminal of Gα₁₄ is important for the interaction with TPR1 and the activation of PLCβ. Collectively, results from the present study show that G_i-coupled receptors can employ Gα₁₄ in endogenous cellular systems for NFκB and STAT3 activation through G₁₄/TPR1 interaction and activation of the Ras/ERK signaling pathway. By means of G₁₄-regulated pathways, many GPCRs may possess the ability to modulate pro-inflammatory responses as well as other immune responses under physiological conditions.