Gβ₃Is Required for Normal Light ON Responses and Synaptic Maintenance

Abstract

Heterotrimeric G-proteins, comprising Gα and Gβγ subunits, couple metabotropic receptors to various downstream effectors and contribute to assembling and trafficking receptor based signaling complexes. A G-protein β-subunit, Gβ3 plays a critical role in several physiological processes as a polymorphism in its gene is associated with a risk factor for several disorders. Retinal ON bipolar cells express Gβ3, and they provide an excellent system to study its role. In the ON bipolar cells, mGluR6 inverts the photoreceptor’s signal via a cascade in which glutamate released from photoreceptors closes the TRPM1 channel. This cascade is essential for vision since deficiencies in its proteins lead to complete congenital stationary night blindness. Here we report that Gβ3 participates in the G-protein heterotrimer that couples mGluR6 to TRPM1. Gβ3 deletion in mouse greatly reduces the light response under both scotopic and photopic conditions, but it does not eliminate it. In addition, Gβ3 deletion causes mislocalization and downregulation of most cascade elements and modulators. Furthermore, Gβ3 may play a role in synaptic maintenance since in its absence, the number of invaginating rod bipolar dendrites is greatly reduced, a deficit that was not observed at 3 weeks, the end of the developmental period.

Kir2.4 Surface Expression and Basal Current Are Affected by Heterotrimeric G-Proteins

“…As shown previously, staining for mGluR6 was also slightly reduced (Fig. 8, right column) (26). Unlike Gnb3-null retina, staining of Gnao1 (gene encoding G␣ o1 )-null retina was not much different from the wild type (data not shown).…”

“…A role for G␤␥ in trafficking is also supported by studies in neural tissue. We have recently shown that in retinal ON bipolar cells lacking G␤3 (a subunit that mediates their light responses by coupling the metabotropic mGluR6 receptor to the TRPM1 channel), numerous elements that play an important role in the mGluR6 cascade are downregulated or redistributed (26). This includes not only the G-protein subunit partners, but also the receptor mGluR6 and the channel TRPM1.…”

Trpm1

“…A G-protein β subunit, Gβ3 3 , is expressed in ON-bipolar cells and plays an essential role for proper localization of mGluR6 and TRPM1 on rod bipolar dendrites (Dhingra et al 2012). Activation of PKCα reduces the inhibition of Trpm1 function by Mg 2+ (Rampino and Nawy 2011).…”

The Transduction Cascade in Retinal ON-Bipolar Cells: Signal Processing and Disease

“…A strong body of evidence indicates that Gβ3 constitutes the major isoform involved in ON-BC signal transduction. Gβ3 is expressed prominently and specifically in ON-BCs (Dhingra et al 2012, Huang et al 2003, Peng et al 1992) and its knockout severely reduces the amplitude of depolarizing responses of both ON-RBCs and ON-CBCs (Dhingra et al 2012). Similarly, Gγ13 was described as the most prominent isoform present in ON-BCs (Dhingra et al 2008, Huang et al 2003).…”