Sarah R. Wilson

TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch

Itch, the unpleasant sensation that evokes a desire to scratch, accompanies numerous skin and nervous system disorders. In many cases, pathological itch is insensitive to antihistamine treatment. Recent studies have identified members of the Mas-related G protein–coupled receptor (Mrgpr) family that are activated by mast cell mediators and promote histamine-independent itch. MrgprA3 and MrgprC11 act as receptors for the pruritogens chloroquine and BAM8–22, respectively. However, the signaling pathways and transduction channels activated downstream of these pruritogens are largely unknown. We found that TRPA1 is the downstream target of both MrgprA3 and MrgprC11 in cultured sensory neurons and heterologous cells. TRPA1 is required for Mrgpr-mediated signaling, as sensory neurons from TRPA1-deficient mice exhibited markedly diminished responses to chloroquine and BAM8–22. Similarly, TRPA1-deficient mice displayed little to no scratching in response to these pruritogens. Our findings indicate that TRPA1 is an essential component of the signaling pathways that promote histamine-independent itch.

Why we scratch an itch: the molecules, cells and circuits of itch

Itch is described as an irritating sensation that triggers a desire to scratch. However, this definition hardly seems fitting for the millions of people who suffer from intractable itch. Indeed, the Buddhist philosopher Nā´áäāgārjuna more aptly stated, “There is pleasure when an itch is scratched. But to be without an itch is more pleasurable still.” Chronic itch is widespread and very difficult to treat. In this review we focus on the molecules, cells and circuits in the peripheral and central nervous systems that drive acute and chronic itch transmission. Understanding the itch circuitry is critical to developing new therapies for this intractable disease.

Silencing of Odorant Receptor Genes by G Protein βγ Signaling Ensures the Expression of One Odorant Receptor per Olfactory Sensory Neuron

Olfactory sensory neurons express just one out of a possible ∼ 1,000 odorant receptor genes, reflecting an exquisite mode of gene regulation. In one model, once an odorant receptor is chosen for expression, other receptor genes are suppressed by a negative feedback mechanism, ensuring a stable functional identity of the sensory neuron for the lifetime of the cell. The signal transduction mechanism subserving odorant receptor gene silencing remains obscure, however. Here, we demonstrate in the zebrafish that odorant receptor gene silencing is dependent on receptor activity. Moreover, we show that signaling through G protein βγ subunits is both necessary and sufficient to suppress the expression of odorant receptor genes and likely acts through histone methylation to maintain the silenced odorant receptor genes in transcriptionally inactive heterochromatin. These results link receptor activity with the epigenetic mechanisms responsible for ensuring the expression of one odorant receptor per olfactory sensory neuron.

Interactions between keratinocytes and somatosensory neurons in itch.

Keratinocytes are epithelial cells that make up the stratified epidermis of the skin. Recent studies suggest that keratinocytes promote chronic itch. Changes in skin morphology that accompany a variety of chronic itch disorders and the multitude of inflammatory mediators secreted by keratinocytes that target both sensory neurons and immune cells highlight the importance of investigating the connection between keratinocytes and chronic itch. This chapter addresses some of the most recent data and models for the role keratinocytes play in the development and maintenance of chronic itch.

Compelling Passwords from Third Parties: Why the Fourth and Fifth Amendments Do Not Adequately Protect Individuals when Third Parties are Forced to Hand Over Passwords

In 2012, the FBI served a search warrant on Google when a suspect––a user of Google’s phone services––refused to answer any questions about his cellphone, or provide the agents with the password to unlock it. The search warrant compelled Google to hand over the password information and other identifying information for the cellphone (account log-in, password reset, and manufacturer default code), which Google refused to do. Google’s refusal implicates a host of issues regarding our current understanding of privacy and self-incrimination protections and concerns legal scholars with what will happen to these doctrines if the government can simply bypass an individual and obtain passwords from a third party. This Article only begins to scratch the surface of this complex debate by analyzing the extent to which the Fourth and Fifth Amendments protect individuals when the government forces third parties to hand over their passwords, and will illustrate why these amendments do not adequately protect individuals in these situations. With constantly evolving technology and almost daily reports of the government accessing electronic communications and communication records, the time is ripe for Congress to legislate the issue of the government compelling private information, such as passwords, from third parties.

Itching for relief

Little is known about the molecular and cellular mechanisms underlying acute and chronic itch. A new technique for silencing peripheral itch neurons defines two independent itch circuits that transmit signals to the CNS.