Glowing pathways within a cell representing intracellular trafficking guided by a receptor protein acting as a GPS.

Unlocking the Secrets Within: How Cellular GPS Influences Health and Disease

Lena Voss in Health & Wellness December 2025 • 4 min read.

"Delving into the hidden world of subcellular localization of the (Pro)renin receptor ((P)RR/ATP6ap2), revealing its profound impact beyond blood pressure regulation."

For years, the renin-angiotensin system (RAS) was understood as a straightforward system for controlling blood pressure through circulating hormones. Renin, an enzyme within this system, was thought to be the active player, while its precursor, prorenin, was considered inactive. This view, however, has dramatically shifted with the discovery of local RAS activity within tissues and the revelation of new components with unexpected roles.

Central to this shift is the (Pro)renin Receptor ((P)RR/ATP6ap2), initially identified in 1996 for its ability to bind renin. This receptor has revolutionized our understanding, evolving from a simple mediator of cellular effects by (pro)renin to a protein with broad and essential intracellular functions. While (P)RR was first recognized for its role in mediating the effects of (pro)renin, scientists are now realizing it has a much wider range of functions within the cell.

Recent evidence suggests that (P)RR's role as a cell surface receptor may be secondary to more fundamental functions inside the cell. Studies have revealed that (P)RR primarily resides within intracellular organelles, prompting a re-evaluation of its function. In light of this, researchers are directing their focus toward understanding the detailed subcellular distribution of (P)RR and how its location relates to its various functions.

Where is (P)RR Hiding? Unveiling Subcellular Secrets

Glowing pathways within a cell representing intracellular trafficking guided by a receptor protein acting as a GPS.

The (Pro)renin receptor ((P)RR/ATP6ap2) was initially discovered in human mesangial cells and later cloned in 2002. The protein, encoded by the ATP6AP2 gene, consists of 350 amino acids, predicting a mass of around 37 kDa. Its structure includes two hydrophobic domains, suggesting it is a type I transmembrane protein. Researchers have confirmed this structure, showing that (P)RR has an N-terminal signal peptide, an extracellular domain for (pro)renin binding, a single transmembrane domain, and a short cytoplasmic domain.

Shedding events involving proteases like furin and ADAM19 can generate shorter forms of (P)RR within the Golgi apparatus. This process results in:

A soluble (P)RR of 28-29 kDa, corresponding to the first 278 amino acids.
A segment including the transmembrane domain and the C-terminal tail.

While initial studies suggested (P)RR is expressed on the cell surface, allowing it to bind (pro)renin and trigger cellular responses, there's growing evidence that (P)RR's primary location is inside the cell. This intracellular presence suggests it plays a role beyond just a surface receptor. This raises questions about whether the protein's main job is inside cells, not just on the surface.

The Road Ahead: New Directions in (P)RR Research

While the precise functions of (P)RR are still being investigated, its involvement in basic cellular processes like intracellular trafficking is becoming increasingly clear. Future research focusing on how this protein moves within the cell may not only validate known functions but also reveal unexpected roles. Understanding the intricate functions and locations of (P)RR promises to unlock new strategies for treating a range of diseases and improving overall health.

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Everything You Need To Know

What is the (Pro)renin receptor ((P)RR/ATP6ap2) and what was its initially understood function?

The (Pro)renin receptor ((P)RR/ATP6ap2) is a protein, encoded by the ATP6AP2 gene, that was initially identified in 1996. Initially, the function of (P)RR was understood to be primarily involved in blood pressure control. It was recognized for its ability to bind renin and mediate the cellular effects of (pro)renin within the renin-angiotensin system (RAS). This binding was thought to trigger cellular responses related to blood pressure regulation.

How has our understanding of the renin-angiotensin system (RAS) and the role of (P)RR changed over time?

Our understanding of the renin-angiotensin system (RAS) has evolved significantly. Initially, the RAS was viewed as a straightforward system, mainly responsible for blood pressure control via circulating hormones. Renin, an enzyme, was considered the active player while its precursor, prorenin, was thought inactive. However, the discovery of local RAS activity within tissues and the expanded functions of (P)RR have changed this view. The (Pro)renin receptor's role has been expanded from a simple mediator of (pro)renin's effects to one with essential intracellular functions. Now scientists are focused on how (P)RR's location inside the cell impacts its various roles.

Where is the (Pro)renin receptor ((P)RR/ATP6ap2) located within the cell, and how does this impact its function?

The (Pro)renin receptor ((P)RR/ATP6ap2) is primarily found within intracellular organelles, challenging the initial assumption that its main function was on the cell surface. While it can bind (pro)renin on the cell surface, growing evidence suggests its primary location and function are inside the cell. This intracellular localization suggests a broader range of roles beyond acting as a surface receptor, with a focus now on how its location relates to its various functions within different cellular compartments. Understanding the precise locations of (P)RR within cells and its impact on overall health is an ongoing area of research.

What are the structural characteristics of the (Pro)renin receptor ((P)RR/ATP6ap2), and what are the implications of its structure?

The (Pro)renin receptor ((P)RR/ATP6ap2) is a protein consisting of 350 amino acids, with a predicted mass of around 37 kDa. Its structure includes two hydrophobic domains, indicating it is a type I transmembrane protein. Researchers have confirmed this structure, showing an N-terminal signal peptide, an extracellular domain for (pro)renin binding, a single transmembrane domain, and a short cytoplasmic domain. This structural information indicates that (P)RR has distinct domains, allowing it to interact with various molecules both inside and outside the cell. The shedding events that produce shorter forms, like the 28-29 kDa soluble form, further highlight the functional versatility of the receptor.

How does the processing of (P)RR within the Golgi apparatus impact its structure and function, and what is the direction of future research?

Within the Golgi apparatus, proteases like furin and ADAM19 can generate shorter forms of (P)RR. This process results in a soluble form of (P)RR (28-29 kDa) and a segment including the transmembrane domain and the C-terminal tail. These shorter forms suggest (P)RR's involvement in various cellular processes. Future research is directed toward understanding the detailed subcellular distribution of (P)RR, how this protein moves within the cell, and how these locations relate to its various functions. The exploration of (P)RR promises to unlock new strategies for treating a range of diseases and improving overall health by unlocking the secrets of its function and location.