Biology subjects

He, X. J.

Publications and source records attributed to He, X. J..

6 recordsLinked to original sources

bioRxiv2026

Primary cilia facilitate GPCR neurotransmission through the canonical cAMP cascade

The primary cilium is increasingly recognized to be a discrete site for initiating neurotransmission through G protein-coupled receptors (GPCRs), yet how such neurotransmission is propagated downstream remains unclear. A canonical pathway of downstream GPCR neurotransmission is the cyclic AMP (cAMP) / cAMP-dependent protein kinase (PKA) cascade. While cAMP can be locally generated in cilia and produce important effects that are functionally compartmentalized there, neurotransmission through GPCRs must propagate to effectors outside of cilia. Thus, a prevailing current view is that ciliary neurotransmission is restricted to non-canonical, cAMP-dependent pathways. Revisiting this view, we show here that the primary cilium of striatal medium spiny neurons is a major site from which endogenous D1 dopamine receptors initiate cAMP and PKA activity elevations that propagate throughout the extraciliary cytoplasm. We also show that the primary cilium spatially aligns essentially this entire long-range signaling axis from intercalating with numerous dopaminergic axon varicosities that initiate neurotransmission to enforcing proximity with somatic PKA stores that are activated by cAMP downstream. Together, these results extend the concept of ciliary neurotransmission to dopaminergic signaling in striatal neurons and reveal that, in this system, the primary cilium facilitates rather than restricts neurotransmission through the canonical cAMP / PKA cascade.

neuroscience↗

bioRxiv2026

Temporal coding expands the bandwidth of GPCR-mediated neuromodulation

The advent of modern transcriptomic approaches has revealed a breadth of neuromodulatory G protein-coupled receptor (GPCR) co-expression far exceeding what was previously thought. This raises a fundamental question about neuromodulatory system architecture because there is a much smaller number of available G protein transducers. Does this impose an information bottleneck, or can a single transducer pathway distinguish the effects of different neuromodulators? We addressed this question by focusing on four GPCRs that are natively co-expressed in essentially all hippocampal pyramidal neurons and that signal through the canonical Gs-coupled cyclic AMP (cAMP) cascade. We show that each GPCR produces a similar cAMP elevation upon acute activation but the effects observed at downstream steps diverge, to the point that the GPCRs differ dramatically in their ability to drive a transcriptional response. We also show that they differ in their ability to maintain functional responsiveness, with neuropeptide receptors remaining responsive for hours but monoamine receptors rapidly losing responsiveness. We conclude that the effective chemical bandwidth of cellular neuromodulation by GPCRs is not limited by the number of available transducers, and that there exists additional temporal coding which enables individual neurons to distinguish a richer neuromodulatory input.

neuroscience↗

bioRxiv2023

In vivo photopharmacology with light-activated opioid drugs

Traditional methods for site-specific drug delivery in the brain are slow, invasive, and difficult to interface with recordings of neural activity. Here, we demonstrate the feasibility and experimental advantages of in vivo photopharmacology using "caged" opioid drugs that are activated in the brain with light after systemic administration in an inactive form. To enable bidirectional manipulations of endogenous opioid receptors in vivo, we developed PhOX and PhNX, photoactivatable variants of the mu opioid receptor agonist oxymorphone and the antagonist naloxone. Photoactivation of PhOX in multiple brain areas produced local changes in receptor occupancy, brain metabolic activity, neuronal calcium activity, neurochemical signaling, and multiple pain- and reward-related behaviors. Combining PhOX photoactivation with optical recording of extracellular dopamine revealed adaptations in the opioid sensitivity of mesolimbic dopamine circuitry during chronic morphine administration. This work establishes a general experimental framework for using in vivo photopharmacology to study the neural basis of drug action. HighlightsA photoactivatable opioid agonist (PhOX) and antagonist (PhNX) for in vivo photopharmacology. Systemic pro-drug delivery followed by local photoactivation in the brain. In vivo photopharmacology produces behavioral changes within seconds of photostimulation. In vivo photopharmacology enables all-optical pharmacology and physiology.

neuroscience↗

bioRxiv2021

A caged DAMGO for selective photoactivation of endogenous mu opioid receptors

Photoactivatable drugs and peptides can drive quantitative studies into receptor signaling with high spatiotemporal precision, yet few are compatible with behavioral studies in mammals. We developed CNV-Y-DAMGO, a caged derivative of the mu opioid receptor-selective peptide agonist DAMGO. Photoactivation in the mouse ventral tegmental area produced an opioid-dependent increase in locomotion within seconds of illumination. These results demonstrate the power of in vivo photopharmacology for dynamic studies into animal behavior.

neuroscience↗

bioRxiv2021

Extent and complexity of RNA processing in the development of honey bee queen and worker castes revealed by Nanopore direct RNA sequencing

The distinct honey bee (Apis mellifera) worker and queen castes have become a model for the study of genomic mechanisms of phenotypic plasticity. Prior studies have explored differences in gene expression and methylation during development of the two castes, but thus far no study has performed a genome-wide analysis of differences in RNA processing. To address this here we performed a Nanopore-based direct RNA sequencing with exceptionally long reads to compare the mRNA transcripts between honey bee queen and workers at three points during their larval development. We found thousands of significantly differentially expressed isoforms (DEIs) between queen and worker larvae. Most DEIs contained alternative splicing, and many of them contained at least two types of alternative splicing patterns, indicating complex RNA processing in honey bee caste differentiation. We found a negative correlation between poly(A) length and DEI expression, suggesting that poly(A) tails participate in the regulation of isoform expression. Hundreds of isoforms uniquely expressed in either queens or workers during their larval development, and isoforms were expressed at different points in queen and worker larval development demonstrating a dynamic relationship between isoform expression and developmental mechanisms. These findings show the full complexity of RNA processing and transcript expression in honey bee phenotypic plasticity.

developmental biology↗

bioRxiv2021

Convergent, functionally independent signaling by mu and delta opioid receptors in hippocampal parvalbumin interneurons

Functional interactions between G protein-coupled receptors are poised to enhance neuronal sensitivity to neuromodulators and therapeutic drugs. Mu and Delta opioid receptors (MORs and DORs) can interact when overexpressed in the same cells, but whether co-expression of endogenous MORs and DORs in neurons leads to functional interactions is unclear. Here, we show that both MORs and DORs inhibit parvalbumin-expressing basket cells (PV-BCs) in hippocampal CA1 through partially occlusive signaling pathways that terminate on somato-dendritic potassium channels and presynaptic calcium channels. Using photoactivatable opioid neuropeptides, we find that DORs dominate the response to enkephalin in terms of both ligand-sensitivity and kinetics, which may be due to relatively low expression levels of MOR. Opioid-activated potassium channels do not show heterologous desensitization, indicating that MORs and DORs signal independently. In a direct test for heteromeric functional interactions, the DOR antagonist TIPP-Psi does not alter the kinetics or potency of either the potassium channel or synaptic responses to photorelease of the MOR agonist DAMGO. Thus, despite largely redundant and convergent signaling, MORs and DORs do not functionally interact in PV-BCs. These findings imply that crosstalk between MORs and DORs, either in the form of physical interactions or synergistic intracellular signaling, is not a preordained outcome of co-expression in neurons.

neuroscience↗