ATP Release Channels

Abstract

Adenosine triphosphate (ATP) has been well established as an important extracellular ligand of autocrine signaling, intercellular communication, and neurotransmission with numerous physiological and pathophysiological roles. In addition to the classical exocytosis, non-vesicular mechanisms of cellular ATP release have been demonstrated in many cell types. Although large and negatively charged ATP molecules cannot diffuse across the lipid bilayer of the plasma membrane, conductive ATP release from the cytosol into the extracellular space is possible through ATP-permeable channels. Such channels must possess two minimum qualifications for ATP permeation: anion permeability and a large ion-conducting pore. Currently, five groups of channels are acknowledged as ATP-release channels: connexin hemichannels, pannexin 1, calcium homeostasis modulator 1 (CALHM1), volume-regulated anion channels (VRACs, also known as volume-sensitive outwardly rectifying (VSOR) anion channels), and maxi-anion channels (MACs). Recently, major breakthroughs have been made in the field by molecular identification of CALHM1 as the action potential-dependent ATP-release channel in taste bud cells, LRRC8s as components of VRACs, and SLCO2A1 as a core subunit of MACs. Here, the function and physiological roles of these five groups of ATP-release channels are summarized, along with a discussion on the future implications of understanding these channels.

Keywords: ATP; CALHM; VRAC; VSOR; connexin; ion channel; maxi-anion channel; pannexin; purinergic signaling.

Figure 1

Adenosine triphosphate (ATP) release ion channels. In the presence of physiological levels of Mg²⁺, the majority of ATP molecules exist as MgATP²⁻ anions in both the extracellular and intracellular compartments. Based on the typical extracellular and intracellular MgATP²⁻ concentrations ((MgATP²⁻)_o and (MgATP²⁻)_i, respectively), the equilibrium potential of MgATP²⁻ (E_MgATP²⁻) was calculated. Cx, connexin; PANX1, pannexin 1; CALHM1, calcium homeostasis modulator 1; VRAC, volume-regulated anion channel; MAC, maxi-anion channel.

Figure 2

Action potential-dependent ATP release from type II taste bud cells through voltage-gated CALHM1 channels mediates fast purinergic neurotransmission of sweet, bitter, and umami tastes. Δψ, receptor potential; ER, endoplasmic reticulum; DAG, diacylglycerol; InsP₃, inositol 1,4,5-trisphosphate; PLCβ2, phospholipase β2.