Blood Pressure Regulates Functional Coupling of L-Type Ca2+ Channels: Reimaging the Foundation of Cerebral Blood Flow Control.

Mironova, G. Y.; Baudel, M. M.-A.; Lambride, C.; Kharche, S.; Steven, D.; Lau, J.; MacDougall, K.; Boulton, M.; Schmid, F.; Navedo, M.; Welsh, D. G.

doi:10.64898/2026.03.02.708544

bioRxiv · 10.64898/2026.03.02.708544

Blood Pressure Regulates Functional Coupling of L-Type Ca2+ Channels: Reimaging the Foundation of Cerebral Blood Flow Control.

Mironova, G. Y.·Baudel, M. M.-A.·Lambride, C.·Kharche, S.·Steven, D.·Lau, J.·MacDougall, K.·Boulton, M.·Schmid, F.·Navedo, M.·Welsh, D. G.

View original source ↗Export metadata ↓

Abstract

The myogenic response is the key autoregulatory mechanism setting cerebral blood flow and its mechanistic foundation is intimately tied to depolarization and the voltage gating of L-type Ca2+ channels (CaV1.2). While critical, this study argues for an additional mechanism, that of pressure itself enhancing CaV1.2 activity via cooperative gating and perimembrane trafficking of channels subunits. These novel insights were pursued at the cell level using patch-clamp electrophysiology and advanced microscopy, and then functionally in pressurized arteries through measures of tone and intracellular [Ca2+]i. Key findings were confirmed in mutant mice with disrupted functional coupling and translated into arteries procured from human brain tissue. From cerebral blood flow simulations of semi-realistic microvascular networks, we predict that loss of this alternative mechanism leads to maldistribution of brain blood flow and potentially a diminishment of cognitive function. This study reveals previously unrecognized pressure-sensitive CaV1.2 regulatory mechanism that advances understanding of cerebral blood flow. SignificanceBlood pressure sets base arterial constriction - a response critical for blood flow control in brain. This response is tied to CaV1.2 channels and their presumptive and exclusive activation by voltage, reasoning now under great scrutiny. We establish herein with advance methods, a second mode of CaV1.2 pressure regulation, that of enhanced functional cooperativity among neighboring channels. This novel mechano-response is tied to PKC and its ability to set channel phosphorylation and CaV1.2 trafficking. CaV1.2 pressure regulation was observed in human tissues and its disruption (mutant mice) impaired myogenic tone in the presence of preserved voltage control. Cerebral microvascular modeling highlights that losing this mechanism destabilizes blood flow distribution in brain, the knock-on effect being comprised cognitive function.

Source connections

Published article ↗

Explore related subjects

physiology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Mironova, G. Y., Baudel, M. M.-A., Lambride, C., Kharche, S., Steven, D., Lau, J., MacDougall, K., Boulton, M., Schmid, F., Navedo, M., Welsh, D. G.. 2026-03-04. Blood Pressure Regulates Functional Coupling of L-Type Ca2+ Channels: Reimaging the Foundation of Cerebral Blood Flow Control.. https://doi.org/10.64898/2026.03.02.708544

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Hypothalamic Farnesoid X Receptor deficiency alters energy balance by modulating hepatic glucose production and adipose tissue metabolism through central insulin signaling.

Objectives: The bile acid nuclear receptor Farnesoid X Receptor (FXR, NR1H4) is a major regulator of metabolism and energy homeostasis in peripheral organs. It modulates bile acid, glucose, and lipid metabolism, as well as fat mass and body weight. However, FXR is also expressed in the brain, particularly in the hypothalamus, a key center for the regulation of energy homeostasis. Although one study has demonstrated a role for brain FXR activation in energy balance, its specific hypothalamic role is still unknown. Here, we examined the role of FXR in the mediobasal hypothalamus in the regulation of energy balance. Methods: We used a genetic approach combined with metabolic phenotyping to determine the effect of FXR invalidation in the mediobasal hypothalamus on metabolic parameters involved in the central regulation of energy homeostasis. Results: Our results demonstrate that hypothalamic FXR deficiency induces a positive energy balance, resulting in a reduction in energy expenditure due to alterations in glucose metabolism accompanied by structural changes in white adipose tissues. Conclusion: This study uncovers a previously unrecognized role for hypothalamic FXR in the central homeostatic control of energy balance, providing new insights into its contribution to peripheral glucose metabolism and adipose tissue structural remodeling.

physiology↗

bioRxiv2026

Rad and Phospholamban are Key Drivers of the Ventricular Adrenergic Response and Stress-Induced Arrhythmia

The adrenergic response is a fundamental mechanism that regulates heart rate (chronotropy), cardiac contractility (inotropy) and relaxation (lusitropy). Adrenergic stress is also a recognized trigger of arrhythmia in disease. Yet, our understanding of the underlying molecular basis remains incomplete. Protein kinase A (PKA) and the calcium/calmodulin-dependent kinase II (CaMKII) phosphorylate multiple targets proposed to participate in the adrenergic response, including the GTP-binding protein Rad, phospholamban (PLB) and ryanodine receptor 2 (RyR2). Here we demonstrate that phosphorylation of both Rad and PLB is necessary for inotropy and lusitropy. We show that changes in cardiac contractility and relaxation are primarily dependent on intracellular calcium handling. Finally, we report that Rad and PLB control stress-induced arrhythmogenesis, despite the phosphorylation of other pro-arrhythmic targets. We have identified the essential molecular components of the adrenergic response, resolving a long-standing debate in cardiac excitation-contraction coupling and refining current models of sympathetic regulation in health and disease.

physiology↗

bioRxiv2026

Light-cycle time-restricted feeding remodels a hidden layer of the cardiac transcriptome through sex-specific transcript switching

Light-cycle time-restricted feeding disrupts daily cardiovascular and thermoregulatory rhythms, but the molecular effects of light-cycle time-restricted feeding on the heart have been measured only at the level of total gene expression. We used Oxford Nanopore long-read RNA sequencing to resolve the full-length ventricular transcriptome from male and female mice under ad libitum feeding or light-cycle time-restricted feeding across the 24-hour cycle. Greater than 20% of cardiac transcripts represent unannotated variants of known genes absent from the current GENCODE reference annotation. Light-cycle time-restricted feeding reorganizes transcript usage across hundreds of genes, including genes encoding splicing regulators, largely without changing total gene expression. The genes affected are sex-specific, with fewer than 2% of changes shared at the gene, transcript, and transcript-usage levels. We show that transcript-level regulation is a previously underrecognized component of the cardiac response to altered feeding behavior, undetected by conventional short-read approaches.

physiology↗