# Tuning L-Type Ca Channel Activity in Arterial Smooth Muscle by Kv Channel-Mediated Clustering

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $508,101

## Abstract

Project Summary
Dihydropyridine-sensitive, L-type Cav1.2 and delayed rectifier Kv2.1 channels play critical roles in the
regulation of excitability and contraction in arterial smooth muscle. A salient feature of Cav1.2 channels is that
they form clusters within which they undergo dynamic, reciprocal interactions that allow functional coupling of
adjacent channels and thus amplification of Ca2+ signaling, which is critical to the development of myogenic
tone. At present, however, the mechanisms controlling Cav1.2 clustering are unknown. The Trimmer and
Santana labs have joined forces to address this fundamental issue. New preliminary data from our labs
suggest a novel model that represents a paradigm shift relative to the generally accepted canonical role of
Kv2.1, and K+ channels in general, as acting solely as K+ conducting electrical determinants of the intrinsic
membrane properties of arterial myocytes. In this model, the Kv2.1 channel has a physical role to increase
clustering and thus cooperative gating of Cav1.2 channels. Our data indicate that the balance between the
separable electrical and structural roles of Kv2.1 channels fine tunes membrane potential, Cav1.2 clustering,
functional coupling of these channels, and hence Ca2+ influx, myogenic tone, and, ultimately, blood pressure. A
key finding that underscores the significance of our work is that Kv2.1 expression varies with sex, leading to
significant differences in Ca2+ influx and myogenic tone between female and male arterial myocytes. The
combination of our complementary skill sets allows us to implement a multi-scale systems approach that
involves the use of cellular, molecular, biophysical, imaging, gene editing and whole-animal approaches to
rigorously investigate the mechanisms controlling Kv2.1 and Cav1.2 organization, and how they impact cell,
organ, and whole-body functions under physiological conditions. The project has three specific aims. Aim 1 is
to determine the impact of altered Kv2.1 expression levels on clustering and activity of Cav1.2 channels, and
myogenic tone in arterial smooth muscle, and on blood pressure. Aim 2 is to define the mechanisms underlying
Kv2.1-mediated regulation of Cav1.2 function. Finally, Aim 3 is to use novel genetic models to define the cell
autonomous role of Kv2.1, and its separable conducting and non-conducting functions, in regulating Cav1.2
function, and the myogenic response in arterial smooth muscle cells, and systemic blood pressure. The
proposed studies have the potential of transforming our understanding of how ion channels are organized in
vascular smooth muscle, and provide insights into how arterial diameter and blood pressure are differentially
regulated in females versus males.

## Key facts

- **NIH application ID:** 9954142
- **Project number:** 5R01HL144071-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Luis F Santana
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $508,101
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9954142

## Citation

> US National Institutes of Health, RePORTER application 9954142, Tuning L-Type Ca Channel Activity in Arterial Smooth Muscle by Kv Channel-Mediated Clustering (5R01HL144071-03). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9954142. Licensed CC0.

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