Pharacine

G protein-coupled receptors (GPCRs) constitute the largest superfamily of integral membrane protein receptors. As signal detectors, the several 100 known GPCRs are responsible for sensing the plethora of endogenous ligands that are critical for the functioning of our endocrine system. Although GPCRs are typically considered as detectors for first messengers in classical signal transduction pathways, they seldom operate in isolation in complex biological systems. Intercellular communication between identical or different cell types is often mediated by autocrine or paracrine signals that are generated upon activation of specific GPCRs. In the context of energy homeostasis, the distinct complement of GPCRs in each cell type bridges the autocrine and paracrine communication within an organ, and the various downstream signaling mechanisms regulated by GPCRs can be integrated in a cell to produce an ultimate output. GPCRs thus act as gatekeepers that coordinate and fine-tune a response. By examining the role of GPCRs in activating and receiving autocrine and paracrine signals, one may have a better understanding of endocrine diseases that are associated with GPCR mutations, thereby providing new insights for treatment regimes.

Steroid hormones coordinate and control the development and function of many organs and are implicated in many pathological processes. Progesterone signaling, in particular, is essential for several important female reproductive functions. Physiological effects of progesterone are mediated by its cognate receptor, expressed in a subset of cells in target tissues. Experimental evidence has accumulated that progesterone acts through both cell intrinsic as well as paracrine signaling mechanisms. By relegating the hormonal stimulus to paracrine signaling cascades the systemic signal gets amplified locally and signaling reaches different cell types that are devoid of hormone receptors. Interestingly, distinct biological responses to progesterone in different target tissues rely on several tissue-specific and some common paracrine factors that coordinate biological responses in different cell types. Evidence is forthcoming that the intercellular signaling pathways that control development and physiological functions are important in tumorigenesis.

Autocrine and paracrine signaling in the kidney adds an extra level of diversity and complexity to renal physiology. The extensive scientific production on the topic precludes easy understanding of the fundamental purpose of the vast number of molecules and systems that influence the renal function. This systematic review provides the broader pen strokes for a collected image of renal paracrine signaling. First, we recapitulate the essence of each paracrine system one by one. Thereafter the single components are merged into an overarching physiological concept. The presented survey shows that despite the diversity in the web of paracrine factors, the collected effect on renal function may not be complicated after all. In essence, paracrine activation provides an intelligent system that perceives minor perturbations and reacts with a coordinated and integrated tissue response that relieves the work load from the renal epithelia and favors diuresis and natriuresis. We suggest that the overall function of paracrine signaling is reno-protection and argue that renal paracrine signaling and self-regulation are two sides of the same coin. Thus local paracrine signaling is an intrinsic function of the kidney, and the overall renal effect of changes in blood pressure, volume load, and systemic hormones will always be tinted by its paracrine status.