Integrative Signaling Networks of Membrane Guanylate Cyclases: Biochemistry and Physiology

Abstract

This monograph presents a historical perspective of cornerstone developments on the biochemistry and physiology of mammalian membrane guanylate cyclases (MGCs), highlighting contributions made by the authors and their collaborators. Upon resolution of early contentious studies, cyclic GMP emerged alongside cyclic AMP, as an important intracellular second messenger for hormonal signaling. However, the two signaling pathways differ in significant ways. In the cyclic AMP pathway, hormone binding to a G protein coupled receptor leads to stimulation or inhibition of an adenylate cyclase, whereas the cyclic GMP pathway dispenses with intermediaries; hormone binds to an MGC to affect its activity. Although the cyclic GMP pathway is direct, it is by no means simple. The modular design of the molecule incorporates regulation by ATP binding and phosphorylation. MGCs can form complexes with Ca2+-sensing subunits that either increase or decrease cyclic GMP synthesis, depending on subunit identity. In some systems, co-expression of two Ca2+ sensors, GCAP1 and S100B with ROS-GC1 confers bimodal signaling marked by increases in cyclic GMP synthesis when intracellular Ca2+ concentration rises or falls. Some MGCs monitor or are modulated by carbon dioxide via its conversion to bicarbonate. One MGC even functions as a thermosensor as well as a chemosensor; activity reaches a maximum with a mild drop in temperature. The complexity afforded by these multiple limbs of operation enables MGC networks to perform transductions traditionally reserved for G protein coupled receptors and Transient Receptor Potential (TRP) ion channels and to serve a diverse array of functions, including control over cardiac vasculature, smooth muscle relaxation, blood pressure regulation, cellular growth, sensory transductions, neural plasticity and memory.

Ca2+-Sensor Neurocalcin δ and Hormone ANF Modulate ANF-RGC Activity by Diverse Pathways: Role of the Signaling Helix Domain

“…Kick started by historic discovery of the prototype ANF-RGC (Atrial Natriuretic Factor Receptor Guanylate Cyclase) ( Paul, 1986 ; Paul et al, 1987 ), the membrane guanylate cyclase (MGC) field has expanded to constitute a family of seven - -ANF-RGC, CNP-RGC, STa-RGC, ROS-GC1, ROS-GC2, ONE-GC and GC-G [reviewed (including) in terminology: ( Sharma et al, 2016 )]. By synthesizing cellular second messenger cyclic GMP the family is interlocked with the diverse physiological processes ranging from cardiac vasculature to cellular growth, sensory transductions, neural plasticity, temperature sensing and pineal-linked brain functions (reviewed and Figure 10 in Sharma et al, 2016 ).…”

“…Kick started by historic discovery of the prototype ANF-RGC (Atrial Natriuretic Factor Receptor Guanylate Cyclase) ( Paul, 1986 ; Paul et al, 1987 ), the membrane guanylate cyclase (MGC) field has expanded to constitute a family of seven - -ANF-RGC, CNP-RGC, STa-RGC, ROS-GC1, ROS-GC2, ONE-GC and GC-G [reviewed (including) in terminology: ( Sharma et al, 2016 )]. By synthesizing cellular second messenger cyclic GMP the family is interlocked with the diverse physiological processes ranging from cardiac vasculature to cellular growth, sensory transductions, neural plasticity, temperature sensing and pineal-linked brain functions (reviewed and Figure 10 in Sharma et al, 2016 ). These processes are compromised by natural mutations incurred in their key genes (discussed in Duda et al, 2018 ); a few examples are: CNP-RGC-R 819 C causes acromesomelic dysplasia ( Vasques et al, 2013 ; Nakao et al, 2015 ); and more than 100 ROS-GC1 mutations result in retinal dystrophies, mainly Leber’s congenital amaurosis (LCA1) and cone-rod degeneration (CORD6) ( Perrault et al, 1996 , 1999 ; Kelsell et al, 1998 ; Wilkie et al, 2000 ; Rozet et al, 2001 ; Hunt et al, 2010 ; Gradstein et al, 2016 ).…”

Receptor Guanylyl Cyclases in Sensory Processing

“…The enzyme activity differed in the two fractions (8–10) and was subsequently purified from both fractions (11, 12). The cDNAs of both were cloned (13–16), and GCs are classified into two groups: receptor guanylyl cyclase (rGC, also called membrane GC or receptor-type GC) and soluble GC (sGC) (2, 17). The soluble forms have been shown to exist as heterodimers, consisting of α and β subunits, and containing heme as a prosthetic group.…”

“…Apart from the overall structural differences, GCD monomers of sGCs and rGCs have the same protein fold as the mammalian adenylyl cyclase (AC) catalytic domain (3). rGCs can be activated either by extracellular ligands, such as natriuretic peptides and uroguanylin in GC-A, GC-B, and GC-C, or by intracellular calcium-binding proteins, such as guanylyl cyclase-activating proteins (GCAPs) in GC-E (also known as RetGC-1) and GC-F (RetGC-2) (2, 17, 22). …”

“…Based on recent structural studies of rGCs in mammals and other organisms, molecular mechanisms underlying activation of rGCs are also discussed. rGCs of other organisms have been reviewed elsewhere (2–4, 17, 22, 29). …”