Abstract
Ca2+ signaling influences nearly every aspect of cellular life. Transient receptor potential (TRP) ion channels have emerged as cellular sensors for thermal, chemical and mechanical stimuli and are major contributors to Ca2+ signaling, playing an important role in diverse physiological and pathological processes. Notably, TRP ion channels are also one of the major downstream targets of Ca2+ signaling initiated either from TRP channels themselves or from various other sources, such as G-protein coupled receptors, giving rise to feedback regulation. TRP channels therefore function like integrators of Ca2+ signaling. A growing body of research has demonstrated different modes of Ca2+-dependent regulation of TRP ion channels and the underlying mechanisms. However, the precise actions of Ca2+ in the modulation of TRP ion channels remain elusive. Advances in Ca2+ regulation of TRP channels are critical to our understanding of the diversified functions of TRP channels and complex Ca2+ signaling.
Highlights
Transient receptor potential (TRP) ion channels are a large family of cation channels consisting of six mammalian subfamilies: TRPV, TRPM, TRPA, TRPC, TRPP and TRPML [1]
TRPV1–4 are mainly expressed in the sensory ganglia and skin responsible for thermo-sensation, pain and itch, whilst TRPV5 and TRPV6 are primarily expressed in the kidney and gastrointestinal tract and play a major role in Ca2+ absorption and homeostasis [3,5,6]
The TRPM subfamily is the largest, consisting of eight members broadly expressed in a variety of cells and tissues, such as sensory ganglia, pancreatic beta cells, immune cells, the tongue, heart and kidney, and are critical for sensory physiology (e.g., heat (TRPM3), cold (TRPM8), taste (TRPM5) and light (TRPM1) sensing and detection) [5], insulin release (TRPM2, TRPM4 and TRPM5) [7,8], Mg2+ homeostasis (TRPM6 and TRPM7), ischemic injury and inflammatory responses (TRPM2, TRPM4) [9]
Summary
Transient receptor potential (TRP) ion channels are a large family of cation channels consisting of six mammalian subfamilies: TRPV, TRPM, TRPA, TRPC, TRPP and TRPML [1]. Disrupting CaM binding to C-CaMBD through mutation abolished Ca2+-induced potentiation of TRPV4 and significantly slowed down channel activation rate [65]. It was initially proposed that Ca2+/CaM binding displaces and releases an inhibitory interdomain interaction with C-CaMBD from the N-terminus of TRPV4, similar to CaM-dependent activation of CaMKII [17] This idea was supported by the finding that disrupting the interaction between the N-terminus and C-CaMBD enhanced TRPV4 currents, as did Ca2+/CaM, and abolished Ca2+-induced channel potentiation [66]. A different autoinhibitory domain in the C-terminus (795–804), immediately upstream of C-CaMBD, was demonstrated to be critical Deleting this domain resulted in constitutive channel activity and eliminated Ca2+/CaM modulation; and secondly, two gain-of-function TRPV4 mutants, E797K and. Whether it is mediated by Ca2+/CaM as suggested above remains an open question
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