Accessory proteins for heterotrimeric G-protein: Implication in the cardiovascular system

Abstract

The G-protein signaling system plays an important role in controlling cellular responses to numerous hormones and neurotransmitters involved in homeostasis of the cardiovascular system. In addition to traditional determinants of G-protein signaling such as the G-protein-coupled receptor (GPCR), heterotrimeric G-proteins and effectors, accumulating data indicate the existence of entities that directly regulate the activation status of G-proteins independent of GPCR. To date, there have been a number of reports on accessory proteins that influence GDP dissociation, affect nucleotide exchange at the Gα subunit, alter subunit interactions within heterotrimeric Gαβγ independent of nucleotide exchange, or form complexes with Gα or Gβγ independent of the typical Gαβγ heterotrimer. Such proteins may provide an additional signal input to the G-protein signaling system in the absence of GPCR or may act as an alternative binding partner of G-protein subunits serving unknown roles of G-proteins in cells. Accumulating information suggests that accessory proteins for G-proteins are actually involved in the regulation of the signaling system to maintain homeostasis and the dynamic responses to physiological and pathological challenges. It is likely that alterations in signal processing may be achieved by the modulation of signal processing within the cell using accessory proteins for G-proteins. The loss of regulation of this system, leading to inappropriate activation or inactivation of G-protein signaling, is strongly implicated in various human diseases. In this review, we update current information and discuss different accessory proteins for heterotrimeric G-proteins in terms of their involvement in the regulation of the cardiovascular system. Such information may contribute to uncovering mechanisms underlying cardiovascular disease as well as the development of novel therapeutic approaches to human disease.

Introduction

Signal processing via heterotrimeric G-proteins is one of the most widely used systems for information transfer across the cell membrane. This system is essential for maintaining tissue homeostasis, but is also involved in the development of cardiac hypertrophy [1], remodeling of the heart [1], ischemic preconditioning [2], [3], and angiogenesis [4]. In addition, many of the therapeutic interventions are used in the management of cardiovascular disease targeting G-protein signaling systems via cell surface G-protein-coupled receptors (GPCRs).

In this system, seven transmembrane domain GPCRs are activated by extracellular stimuli, such as hormones and neurotransmitters, inducing a conformational change in the Gα subunit, and then catalyzing GDP release from Gα (Fig. 1). Binding of GTP to Gα destabilizes Gαβγ complex, leading to a structural rearrangement of Gα-GTP, Gβγ and the receptor. This is followed by Gα-GTP disassociation from the receptor and Gβγ. Both subunits, Gα-GTP and Gβγ, stimulate distinct downstream effector molecules including adenylyl cyclases, phospholipases, ion channels, and protein kinases [5], [6], [7]. The activation of the signaling pathway is terminated when Gα hydrolyzes GTP to GDP by its intrinsic guanosine triphosphatase (GTPase) activity; it then reassociates with Gβγ, thus completing the cycle. Reassociation of Gβγ with Gα-GDP terminates interactions of effector molecules. Gβγ facilitates the coupling of Gα to GPCR and also acts as a guanine nucleotide inhibitor (GDI) for Gα-GDP, slowing spontaneous exchange of GDP for GTP (Table 1).

These events are dynamically regulated to optimize signal specificity, maximize signal efficiency and integrate diverse stimuli. As a consequence of this central role in signal integration, the subtle adaptations or maladaptations that occur in response to both physiological and pathophysiological challenges can play a key role in the manner in which the effector cell responds to such challenges. Regulations of the G-protein system include the segregation of specific signaling molecules in cell microdomains, receptor phosphorylation and internalization, and crosstalk between signaling pathways. In addition to these, a number of proteins that regulate the basal activation state of G-proteins independently of cell surface GPCR have been discovered. Such accessory proteins influence the activation or deactivation of the Gα subunit and alter subunit interactions within heterotrimeric Gαβγ independent of nucleotide exchange, or form complexes with Gα or Gβγ independent of the typical Gαβγ heterotrimer. Accessory proteins for G-proteins may provide an additional signal input to the G-protein signaling system in the absence of GPCR or may act as an alternative binding partner of G-protein subunits serving unknown roles of G-proteins in cells. In previous work, we evolved the observation of such accessory proteins and tuning of the signaling system concerned based on cell-specific differences [8], [9] and the subsequent biochemical characterization of such differences [9], [10], [11], [12]. We later addressed the impact of accessory proteins in terms of system adaptation of the GPCR system [13] and identified novel accessory proteins for G-proteins induced in the myocardium in response to transient ischemia [14].

An adaptation of the signaling system is critical for maintaining homeostasis and the dynamic responses to physiological and pathological challenges. It is likely that subtle alterations in signal processing may be achieved by discrete modulation of signal processing within the cell using accessory proteins for G-proteins. Current information suggests that accessory proteins for G-proteins are actually involved in the regulation of the signaling system for maintaining homeostasis and the dynamic responses to physiological and pathological challenges. The loss of regulation of this system, leading to inappropriate activation or inactivation of G-protein signaling, is strongly implicated in various human diseases.

In this review, we update current information and discuss various accessory proteins for heterotrimeric G-proteins in terms of their involvement in the regulation of the cardiovascular system (Table 2). Such information may contribute to uncovering the mechanisms underlying cardiovascular disease as well as the development of a novel therapeutic approach to human disease.