Whirlin increases TRPV1 channel expression and cellular stability

Abstract

The expression and function of TRPV1 is influenced by its interaction with cellular proteins. Here, we identify whirlin, a cytoskeletal PDZ-scaffold protein implicated in hearing, vision and mechanosensory transduction, as an interacting partner of TRPV1. Whirlin associates with TRPV1 in cell lines and in primary cultures of rat nociceptors. Whirlin is expressed in 55% of mouse sensory C-fibers, including peptidergic and non-peptidergic nociceptors, and co-localizes with TRPV1 in 70% of them. Heterologous expression of Whirlin increased TRPV1 protein expression and trafficking to the plasma membrane, and promoted receptor clustering. Silencing Whirlin expression with siRNA or blocking protein translation resulted in a concomitant degradation of TRPV1 that could be prevented by inhibiting the proteasome. The degradation kinetics of TRPV1 upon arresting protein translation mirrored that of Whirlin in cells co-expressing both proteins, suggesting a parallel degradation mechanism. Noteworthy, Whirlin expression significantly reduced TRPV1 degradation induced by prolonged exposure to capsaicin. Thus, our findings indicate that Whirlin and TRPV1 are associated in a subset of nociceptors and that TRPV1 protein stability is increased through the interaction with the cytoskeletal scaffold protein. Our results suggest that the Whirlin-TRPV1 complex may represent a novel molecular target and its pharmacological disruption might be a therapeutic strategy for the treatment of peripheral TRPV1-mediated disorders.

TRPV1 channels and the progesterone receptor Sig-1R interact to regulate pain

“…As mentioned before, Whirlin is a protein involved in the stability and increased expression of TRPV1 (13). In this respect, the interaction between TRPV1 and Whirlin confers resistance to lysosomal degradation by prolonged exposure to capsaicin.…”

“…Among such proteins are the A-kinase anchor protein (AKAP79/150) (9), GABAA receptor-associated protein (10), beta 2 subunit of voltagegated K + channel (Kvβ2) (11), and the ankyrin-rich membranespanning protein/kinase D-interacting substrate adaptor protein (ARMS) (12). Another protein with which TRPV1 interacts is Whirlin, a cytoskeletal PDZ scaffold protein that increases ion channel expression and stability (13). However, to date, the interactions of TRPV1 with proteins such as chaperones that could potentially regulate trafficking to the plasma membrane, as well as the physiological implications of this regulation, have not been described.…”

Lipids as central modulators of sensory TRP channels

“…In addition to this complexity, the function of these channels is critically regulated by the formation of signaling complexes (known as signalplexes) with a variety of accessory and/or signaling proteins [25][26][27][28][29]. Recent and promising findings suggest that manipulation of these interactions between TRP channels and their regulatory proteins can be exploited for therapeutic intervention [30].…”

Identification of whirlin domains interacting with espin: A study of the mechanism of Usher syndrome type�II

“…Studies suggest that whirlin is a scaffold protein and may be essential for the assembly of the USH2 complex (6,14). Therefore, it is critical to identify proteins that interact with whirlin and that are part of the USH2 complex (15–18).…”