Biology subjects

Hirsch, J. A.

Publications and source records attributed to Hirsch, J. A..

5 recordsLinked to original sources

bioRxiv2026

The thalamic reticular nucleus provides spatially and temporally tuned inhibition to the lateral geniculate nucleus across species

By proposing a role in spatial attention, Francis Crick piqued interest in the thalamic reticular nucleus (TRN), a GABAergic structure that receives input from relay cells projecting to cortex and feeds back inhibition in return. Importantly, predictions of Crick's hypothesis extend beyond attention to suggest that TRN provides selective, localized inhibition to relay cells and, thus, influences sensory processing per se. To ask if this latter role for TRN holds across species, we compared previous recordings from cat with a novel dataset from mouse, focusing on vision. We estimated receptive field size and structure of reticular cells in the visual sector of TRN and of relay cells in the dorsal lateral geniculate nucleus (dLGN). Cells in both nuclei encoded specific visual features and had receptive fields of comparable size within binocular visual space. Moreover, paired recordings from both structures suggested that TRN is able to promote burst firing in dLGN in addition to modulating spike rate. Thus, TRN is not only important for attentional regulation, but is also able to make fine-tuned contributions to early sensory processing.

neuroscience↗

bioRxiv2026

Gβγ dually regulates the M current via increased channel surface expression and PIP2 sensitivity

The M-current, generated by voltage gated KV7.2/7.3 channels, sets the threshold for neuronal action potential and acts as a key brake on repetitive firing. The M-current is tightly regulated by signaling molecules, such as calmodulin and phosphatidylinositol-4,5-bisphosphate (PIP2). Here, we show that coexpression of the ubiquitous subunit dimer of heterotrimeric G-proteins, G{beta}{gamma}, with KV7.2/7.3 in Xenopus laevis oocytes doubles maximal M-current. This regulation requires free, prenylated, membrane-associated G{beta}{gamma} and operates via two distinct mechanisms: 1) increasing plasma membrane (PM) channel density and 2) stabilizing KV7.2/7.3-PIP2 coupling. Conversely, G{beta}{gamma} scavengers reduce basal KV7.2/7.3 current and weaken PIP2 coupling. Proximity ligation assays confirm colocalization of G{beta}{gamma} and KV7.2/7.3 in the PM. Peptide array and AlphaFold modeling identify putative interaction sites on the channel cytoplasmic domain. Finally, the disease-causing G{beta}1 variant I80N abolished G{beta}{gamma}-induced M-current potentiation. Together, these findings establish G{beta}{gamma} as a significant physiological regulator and potential site of vulnerability in neuronal M-current function.

physiology↗

bioRxiv2025

Structural basis for ATP-driven double-ring assembly of the human mitochondrial Hsp60 chaperonin

The ATP-driven mHsp60:mHsp10 chaperonin system assists protein folding within the mitochondrial matrix of human cells. Substrate protein folding has been proposed to occur through interconnected single- and double-ring pathways. In the absence of nucleotide, mHsp60 exists in equilibrium between free protomers and heptameric single rings, while the formation of double rings requires ATP. Here, we present cryo-electron microscopy structures of mHsp60 in the apo state, bound to ATP, and bound to ATP in complex with the cochaperonin mHsp10. ATP binding to single-ring apo mHsp607 triggers coordinated conformational changes in the intermediate and apical domains, resulting in a highly dynamic apical region within the ring. Extensive inter-subunit rearrangements flatten the equatorial surface of each ring, thereby enabling inter-ring contacts that stitch the rings together to form double-ring mHsp6014. Collectively, these structures define the structural basis of ATP-driven double-ring assembly of a human mitochondrial chaperonin responsible for maintaining mitochondrial protein homeostasis.

biophysics↗

bioRxiv2023

Tripartite interactions of PKA catalytic subunit and C-terminal domains of cardiac Ca2+ channel modulate its β-adrenergic regulation

The adrenergic nervous system augments cardiac contraction by increasing the activity of L-type voltage-gated CaV1.2 channels. Dysregulation of this process is linked to severe cardiac dysfunctions. The signaling cascade involves activation of {beta}-adrenergic receptors, elevation of cAMP levels, separation of protein kinase A (PKA) regulatory subunit (PKAR) from catalytic subunit (PKAC), and phosphorylation of the inhibitory protein Rad leading to increased Ca2+ influx. In cardiomyocytes, the core subunit of CaV1.2 (1C) exists in two forms: full-length (FL) or proteolytically processed (truncated), lacking the distal C-terminus (dCT). Specificity and efficiency in the cascade are believed to emanate from unique protein-protein interactions, such as anchoring PKA (via PKAR) to 1C by A-kinase anchoring proteins (AKAPs). However, most AKAPs do not interact with the truncated 1C, and their role in {beta}AR regulation of cardiac CaV1.2 remains unclear. Here we show that PKAC, independently of PKAR or AKAPs, directly interacts with 1C at two domains in 1C-CT: the proximal and distal C-terminal regulatory domains (PCRD and DCRD), which also interact with each other. Furthermore, we find that DCRD competes with PCRD and reduces its interaction with PKAC. The physiological consequences of these complex interactions are incompletely understood; our data suggest that they may fine-tune the {beta}AR regulation of CaV1.2. We propose that the newly discovered interactions take part in governing colocalization of regulatory proteins within the {beta}AR-CaV1.2 multimolecular signaling complexes in cardiomyocytes.

biochemistry↗

bioRxiv2023

Local interneurons in the murine visual thalamus have diverse receptive fields and can provide feature selective inhibition to relay cells.

By influencing the type and quality of information that relay cells transmit, local interneurons in thalamus have a powerful impact on cortex. To define the sensory features that these inhibitory neurons encode, we mapped receptive fields of optogenetically identified cells in the murine dorsolateral geniculate nucleus. Although few in number, local interneurons had diverse types of receptive fields, like their counterpart relay cells. This result differs markedly from visual cortex, where inhibitory cells are typically less selective than excitatory cells. To explore how thalamic interneurons might converge on relay cells, we took a computational approach. Using an evolutionary algorithm to search through a library of interneuron models generated from our results, we show that aggregated output from different groups of local interneurons can simulate the inhibitory component of the relay cells receptive field. Thus, our work provides proof-of-concept that groups of diverse interneurons can supply feature-specific inhibition to relay cells.

neuroscience↗