“If you always do what you always did, you will always get what you always got.”
“That is a good idea, but it is a new one, and we fear it, so we must reject it.”
Mike Myers as Lothar of the Hill people, Saturday Night Live, 1990
Cellular signaling is not simply a linear process, rather it is influenced by many factors, including localization, time, concentration, and affinity. However, this multifaceted nature of cellular signaling is rarely addressed. The review articles in this series, which focus on nuclear G-protein coupled receptor (GPCR) signaling in cardiac myocytes highlight 1 important aspect of signaling, localization. GPCRs, also known as 7-transmembrane receptors, are integral membrane proteins, and GPCR signaling is traditionally believed to initiate at the cell surface in cardiac myocytes and other cell types to regulate classical “outside-in” signaling. However, over the last several years, it has become clear that GPCRs also localize to and signal at the nuclear membrane in many cell types, including cardiac myocytes, as featured in this series. As with many new ideas, the concept of nuclear GPCR signaling in cardiac myocytes has been met with some resistance. This was typified by a review of an NIH grant proposal (T.D.O.) focused on nuclear GPCR signaling wherein I was told, “We have known for over forty years that… receptors are on the plasma membrane, this cannot be refuted.” However, this is simply an excellent reminder of the words of Albert Einstein or the more humorous version of the same idea by Mike Myers, which is that while advancing new ideas is challenging, it is critical for progress. Therefore, the purpose of this series is to delineate evidence in favor of a more nuanced model of GPCR signaling in cardiac myocytes. To that end, we have collected what we believe to be a series of reviews by leaders in the field that provide substantial evidence for a novel paradigm of nuclear GPCR signaling in cardiac myocytes. In addition to identifying the critical elements required for GPCR signaling at the nucleus in cardiac myocytes, the reviews within this series tackle several important questions including: (1) how signaling is initiated at the nucleus, (2) how signaling components are compartmentalized at the nucleus, (3) how nuclear signals are integrated with cytosolic signals, and (4) what is the physiologic relevance of nuclear GPCR signaling.
This month, the first 3 articles in the series encompass the most proximal aspects of nuclear GPCR signaling from identification of several GPCRs at the nucleus in adult cardiac myocytes to the identification and function of heterotrimeric G-proteins at the nucleus. In the first article, we summarize evidence indicating that endogenous α1-adrenergic receptors (α1-AR) localize to and signal at the nuclear membrane in adult cardiac myocytes.1 Furthermore, we highlight evidence that nuclear localization is required for α1-AR cardiac myocyte contractility and survival, key α1-cardioprotective functions. In the second article, Branco and Allen2 discuss nuclear localization of endothelin, angiotensin, and β-ARs, the development of “caged” ligands to study nuclear GPCR signaling and the physiologic function of nuclear GPCRs with particular focus on regulation of gene transcription. In the third article, Campden et al3 review the roles of nuclear heterotrimeric and monomeric G-proteins and small GTPases, focusing on their nuclear-cytoplasmic shuttling and signaling and regulation of nuclear processes.
Next month, articles 4 through 6 cover downstream signaling, including activation of phospholipase C at the nucleus, nuclear calcium signaling, and the function of A-kinase anchoring proteins (AKAPs) at the nucleus in cardiac myocytes. In the fourth article in the series, Smrcka4 discusses the phospholipase (PLC) isoforms in the nuclear envelope, focusing on his laboratory's recent findings regarding the role of phospholipase-ε, which hydrolyzes phosphotidylinositol 4-phosphate, to regulate cardiac hypertrophy. In the fifth article,5 Ljubojevic and Bers review continuing developments of the role of nuclear calcium signaling in gene regulation in the process of excitation–transcription coupling. They discuss how cardiac myocytes integrate temporal and spatial regulation of calcium in microdomains and the tools to discriminate between calcium signals that might regulate contractile and hypertrophic signals. Finally, in the sixth article,6 Passariello et al discuss the emerging role of AKAP, specifically the mAKAPβ, which is at the core of a “signalosome” responsive to second messenger signaling, stress, and the hypertrophic gene response. They also discuss potential therapeutic strategies targeting mAKAPβ in pathologic cardiac hypertrophy.
In summary, this review series provides a thorough overview of multiple lines of evidence in support of nuclear GPCR signaling. Moving forward, we hope that this influences the field to reconsider how localization might dramatically affect cellular signaling and physiologic function in cardiac myocytes.
1. Wu SC, O'Connell TD. Nuclear compartmentalization of α1-adrenergic receptor signaling in adult cardiac myocytes. J Cardiovasc Pharmacol. 2015;65:91–100.
2. Branco AF, Allen BG. G protein-coupled receptor signalling in cardiac nuclear membranes. J Cardiovasc Pharmacol. 2015;65:101–109.
3. Campden R, Audet N, Hebert TE. Nuclear G protein signalling: new tricks for old dogs. J Cardiovasc Pharmacol. 2015;65:110–122.
4. Smrcka AV. Regulation of Phosphatidylinositol-specific phospholipase C at the nuclear envelope in cardiac myocytes. J Cardiovasc Pharmacol. 2015;65:In press.
5. Ljubojevic S, Bers DM. Nuclear calcium in cardiac myocytes. J Cardiovasc Pharmacol. 2015;65:In press.
6. Passariella CL, Li J, Dodge-Kafka K, et al.. mAKAP—A master scaffold for cardiac remodeling. J Cardiovasc Pharmacol. 2015;65:In press.