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TRPC4 as a coincident detector of Gi/o and Gq/11 signaling: mechanisms and pathophysiological implications

Jaepyo Jeon1, Jin-Bin Tian1, Michael X Zhu1

  • 1Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.

Current Opinion in Physiology
|August 28, 2020
PubMed

Insights

Transient Receptor Potential Canonical 4 (TRPC4) channels detect coincident G-protein signaling. Their activation requires both Gαi/o and Gq/11 pathways, involving specific phospholipase C (PLC) isozymes and ion signals.

Area of Science:

  • Molecular Biology
  • Cell Physiology
  • Ion Channel Function

Background:

  • Transient Receptor Potential Canonical (TRPC) channels are calcium-permeable cation channels crucial for cellular signaling.
  • Most TRPC channels are activated by Gq/11-coupled receptors, but TRPC4 exhibits unique activation requirements.
  • TRPC4 channels necessitate simultaneous stimulation of both Gi/o and Gq/11-coupled receptors for activation.

Purpose of the Study:

  • To elucidate the specific molecular mechanisms underlying TRPC4 channel activation.
  • To investigate the role of coincident Gi/o and Gq/11 signaling in TRPC4 function.
  • To understand the interplay between phospholipase C (PLC) isozymes and G-protein pathways in TRPC4 activation.

Main Methods:

  • Investigated TRPC4 channel activation downstream of phospholipase C (PLC).
  • Examined the role of Gi/o and Gq/11 receptor stimulation in TRPC4 function.
  • Analyzed the contribution of PLCδ1 and other PLC isozymes (e.g., PLCβ) to TRPC4 activation.

Main Results:

  • TRPC4 channels act as coincidence detectors for simultaneous Gi/o and Gq/11 signaling.
  • Activated Gαi/o proteins collaborate with PLCδ1 to promote TRPC4 activation.
  • Gq/11-PLCβ signaling generates initial proton and calcium signals that facilitate PLCδ1 activity and subsequent TRPC4 function.

Conclusions:

  • TRPC4 channels are activated by coincident Gi/o/Gq/11 stimulation or when Gi/o stimulation overlaps with proton and calcium signals.
  • The resulting calcium influx and membrane depolarization convert the inhibitory Gi/o response into excitation.
  • Further research is needed to explore the physiological and pathophysiological implications of Gi/o-mediated TRPC4 activation.
Keywords:
GPCRTRP channelsacidosiscalcium signalingheterotrimeric G proteinsphospholipase C

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