Pores and Selectivity Filters

In this post I will be briefly introducing the classical ideas of ion conduction through membrane proteins. The idea of ion channels as selective pores in the cell membrane is very old but is now understood at atomic detail. So what is a channel? What does an ion conductive pore look like? Here, I will … Continue reading

Hv Physiology: Breast Cancer

In this post I will discuss the role of human Hv1 channels in promoting the pathology and invasiveness of breast cancers. It is well known that cancer consists of normal cells gone awry. As cells age, they can accumulate mutations in their genomes and sometimes these mutations lead to unregulated growth and expansion. The unregulated, … Continue reading

Biochemical Data Constraining the S4 of Hv

In this post I will finish my series on alignments and homology models. Here, I will discuss three different biochemical studies of the voltage-gated proton channel (Hv) that help to delineate the boundaries of the S4 helix. First, I will discuss the structure of the coiled-coil, which limits where along the primary the sequence of … Continue reading

Human Hv1: Architectural Overview

Although voltage-gated proton currents have been measured in cell membranes since the early 1980s (Tomas & Meech, 1982), the genes encoding the voltage-gated proton channels were not discovered until 2006 (Sasaki et al., 2006; Ramsey et al., 2006). What the gene sequence demonstrated was that Hv channels share sequence homology with the voltage-sensor domains (VSDs) of … Continue reading

Is the S4 helix of Hv Short?

In this post, I will elaborate upon a statement I made in last week’s post. There, I discussed how important a proper alignment of the S4 helices in voltage sensor domains (VSDs) is for building accurate homology-based structural models of these domains.  When discussing the potential alignments I stated that “since the different conformations of … Continue reading

The Problem of Aligning S4

Recently, a number of papers have come out that have used sequence homology to generate structural models of human Hv1 (Musset et al,. 2010; Ramsey et al., 2010; Wood et al., 2012). These models have then been used for docking and molecular-dynamics simulations to try to extract some mechanistic insight into the channel function. In … Continue reading

Hv Physiology: Brain Damage

Thanks to the groundbreaking work of Hodgking and Huxley, the most well known physiological role of voltage-gated ion channels is the propagation of the action potential in neurons (Hodgkin & Huxley, 1952). What Hodgkin and Huxley demonstrated was that the action potential is generated by the sequential opening and closing of voltage-gated Na+ and K+ … Continue reading

The Mechanism of Voltage Gating in Potassium Channels? – Part 2 Activation

OK, time for part 2. If you missed part 1 of this two post series check it out here. Just to recap, I am discussing the recent Science paper (April 13th issue) from the D.E. Shaw Research group, entitled “The Mechanism of Voltage Gating in Potassium Channels.” In this paper, Jensen et al. use their … Continue reading

The Mechanism of Voltage Gating in Potassium Channels? – Part 1 Deactivation

In this two part post I will discuss the recent Science paper (April 13th issue) from the D.E. Shaw Research group, entitled “The Mechanism of Voltage Gating in Potassium Channels.” In this paper Jensen et al. use their custom designed supercomputer Anton (named after Anton von Leeuwenhoek, the 18th century microscopist) to perform molecular dynamics … Continue reading

Hv Physiology: Human Male Fertility

The human voltage-gated proton channel Hv1 plays an important physiological role in male fertility in humans. Specifically it is integral for regulation of the internal pH of the sperm cell. The pH of the sperm cytoplasm is a major regulator of sperm cell motility, capacitation, hyperctivation and the acrosome reaction. Each of these processes are … Continue reading