Biology subjects

Agarwal, S. R.

Publications and source records attributed to Agarwal, S. R..

3 recordsLinked to original sources

bioRxiv2025

Neuropeptide Y regulation of L-type Ca2+ channel activity is altered following chronic myocardial infarction

Neuropeptide Y (NPY) is a co-transmitter released from sympathetic neurons along with norepinephrine (NE). It has been observed that cardiac NPY levels are significantly elevated following myocardial infarction (MI), and this has been linked to an increase in ventricular arrhythmogenicity associated with elevated sympathetic tone. However, the effects that NPY has on the electrical activity of ventricular myocytes remain poorly understood. Previous studies have examined the influence of NPY alone on cardiac ion channel function, but not in the presence of NE, which is the situation expected in vivo. Furthermore, no one has examined the effects of NPY on ion channel activity following MI. The present study explored the impact of NPY on the L-type Ca2+ current in ventricular myocytes isolated from the hearts of normal healthy pigs and pigs subjected to MI. We found that NPY alone has a stimulatory effect on the Ca2+ current in myocytes isolated from healthy pigs. However, in the presence of NE, the effect of NPY was inhibitory. The stimulatory effect of NPY alone was blocked by the Y1 receptor antagonist BIBO3304, while the inhibitory effect observed in the presence of NE was blocked by the Y2 receptor antagonist BIIE0246. When the effects of NPY were examined using hearts from pigs following recovery from MI, the stimulatory effect of NPY was absent in myocytes obtained from both remote and border zone areas of infarcted hearts. The inhibitory effect of NPY observed in the presence of NE was also absent in myocytes from remote areas of the infarcted heart. However, the inhibitory effect of NPY observed in the presence of NE was intact in border zone cells. The implications of these results are discussed as they relate to the potential arrhythmogenic effects of NPY following MI. Graphical Abstract. NPY exerts bimodular, context dependent effects on LTCC. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=91 SRC="FIGDIR/small/690298v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@fb248borg.highwire.dtl.DTLVardef@1c3cd9org.highwire.dtl.DTLVardef@1def5b3org.highwire.dtl.DTLVardef@d4bfd5_HPS_FORMAT_FIGEXP M_FIG C_FIG Proposed signaling pathways for diverse effects of NPY in ventricular cardiac myocytes. Norepinephrine (NE) and neuropeptide Y (NPY) co-application results in a Y2/Gi-mediated reduction in {beta}-adrenergic ({beta}AR)/Gs enhanced ICaL, while NPY alone modestly enhances the current via Y1/Gq mechanism. These pathways are regionally altered following chronic MI.

pharmacology and toxicology↗

bioRxiv2025

Nuclear α1A-Adrenergic Receptor Regulation of cAMP Production by an Inside-Out MAP Kinase Signaling Pathway in Cardiac Myocytes

Sympathetic stimulation produces beneficial changes in cardiac function through {beta}-adrenergic receptor ({beta}AR) production of cAMP and subsequent alteration of electrical and mechanical activity. Long term activation of cAMP production also contributes to cardiac remodeling and detrimental changes associated with heart failure. However, sympathetic responses are mediated by the endogenous neurotransmitter norepinephrine (NE), which is also a potent 1-adrenergic receptor (1AR) agonist, and 1AR activation can produce significant effects on the heart as well. What is less clear is how 1- and {beta}-adrenergic responses interact with one another. Previous studies have demonstrated that 1AR activation can inhibit {beta}-adrenergic regulation of electrical and mechanical activity of cardiac myocytes, although the signaling mechanisms involved were not previously known. In the present study, we used FRET-based biosensors in adult rat ventricular myocytes to demonstrate that this crosstalk effect involves inhibition of cAMP production by nuclear 1AARs acting on {beta}ARs found on the plasma membrane. Furthermore, we established that this inside-out signaling mechanism involves a mitogen-activated protein kinase (MAPK) pathway that uncouples {beta}ARs from downstream signaling in a G protein coupled receptor kinase (GRK)/arrestin-dependent manner. These results reveal a novel, non-canonical signaling mechanism contributing to 1AR responses in the heart, and that this effect limits {beta}AR production of cAMP by NE. This mechanism may contribute to the cardioprotective effect previously ascribed to 1AAR activation. These findings also clearly demonstrate the importance of considering the contributions of 1 and {beta}ARs together when studying the influence of the sympathetic nervous system on the heart.

pharmacology and toxicology↗

bioRxiv2023

Coevolution with toxic prey produces functional trade-offs in sodium channels of predatory snakes

Seemingly unrelated traits often share the same underlying molecular mechanisms, potentially generating a pleiotropic relationship whereby selection shaping one trait can simultaneously compromise another. While such functional trade-offs are expected to influence evolutionary outcomes, their actual relevance in nature is masked by obscure links between genotype, phenotype, and fitness. Here, we describe functional trade-offs that likely govern a key adaptation and coevolutionary dynamics in a predator-prey system. Several garter snake (Thamnophis spp.) populations have evolved resistance to tetrodotoxin (TTX), a potent chemical defense in their prey, toxic newts (Taricha spp.). Snakes achieve TTX resistance through mutations occurring at toxin-binding sites in the pore of snake skeletal muscle voltage-gated sodium channels (NaV1.4). We hypothesized that these mutations impair basic NaV functions, producing molecular trade-offs that should ultimately scale up to compromised organismal performance. We investigate biophysical costs in two snake species with unique and independently evolved mutations that confer TTX resistance. We show electrophysiological evidence that skeletal muscle sodium channels encoded by toxin-resistant alleles are functionally compromised. Furthermore, skeletal muscles from snakes with resistance genotypes exhibit reduced mechanical performance. Lastly, modeling the molecular stability of these sodium channel variants partially explains the electrophysiological and muscle impairments. Ultimately, adaptive genetic changes favoring toxin resistance appear to negatively impact sodium channel function, skeletal muscle strength, and organismal performance. These functional trade-offs at the cellular and organ levels appear to underpin locomotor deficits observed in resistant snakes and may explain variation in the population-level success of toxin-resistant alleles across the landscape, ultimately shaping the trajectory of snake-newt coevolution.

evolutionary biology↗