{'fraction_non_alphanumeric': 0.026698309107089886, 'fraction_numerical': 0.003263126668644319, 'mean_word_length': 5.209944751381215, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
A nuclear option? G-protein coupled receptors at the nucleus in cardiac myocytes.

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 a1-adrenergic receptors (a1AR) localize to and signal at the nuclear membrane in adult cardiac myocytes. Furthermore, we highlight evidence that nuclear localization is required for a1-AR cardiac myocyte contractility and survival, key a1-cardioprotective functions. In the second article, Branco and Allen discuss nuclear localization of endothelin, angiotensin, and b-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 al review the roles of nuclear heterotrimeric and monomeric G-proteins and small GTPases, focusing on their nuclearcytoplasmic shuttling and signaling and regulation of nuclear processes.