Activation of steroid‐sensitive TRPM3 channels potentiates glutamatergic transmission at cerebellar Purkinje neurons from developing rats

Abstract

The functional implications of transient receptor potential melastatin 3 (TRPM3) activation, the most recently described member of the melastatin subfamily of cation permeable TRP channels, have begun to be elucidated in recent years. The discovery of TRPM3 activation by the steroid pregnenolone sulfate (PregS) has shed new light on the physiological role of this channel. For example, TRPM3 activation enhances insulin secretion from β pancreatic cells, induces contraction of vascular smooth muscle, and is also involved in the detection of noxious heat. Although TRPM3 expression has been detected in several regions of the developing and mature brain, little is known about the roles of TRPM3 in brain physiology. Here, we demonstrate the abundant expression of TRPM3 steroid-sensitive channels in the developing cerebellar cortex. We also show that TRPM3-like channels are expressed at glutamatergic synapses in neonatal Purkinje cells (PCs). We recently showed that PregS potentiates spontaneous glutamate release onto neonatal PCs during a period of active glutamatergic synapse formation; we now show that this effect of PregS is mediated by TRPM3-like channels. Mefenamic acid, a recently discovered TRPM3 antagonist, blocked the effect of PregS on glutamate release. The PregS effect on glutamate release was mimicked by other TRPM3 agonists (nifedipine and epipregnanolone sulfate) but not by a TRMP3-inactive steroid (progesterone). Our findings identify TRPM3 channels as novel modulators of glutamatergic transmission in the developing brain.

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Data from Trpm3 knockout mice clearly show that TRPM3 plays a role in heat perception and mediates pain responses (Vriens et al, 2011). Finally, TRPM3 is involved in glutaminergic signaling and synaptic plasticity in cerebellar Purkinje cells (Zamudio-Bulcock et al, 2011).…”

Examination of Single Nucleotide Polymorphisms (SNPs) in Transient Receptor Potential (TRP) Ion Channels in Chronic Fatigue Syndrome Patients

“…Additionally, TRPM3 is activated by pregnenolone sulfate, suggesting that it has neuroendocrine effects 62,63 and might also be involved in the regulation of glutamatergic signaling in the brain. 64 These preliminary findings implicate TRP ion channels in the etiology and pathomechanism of CFS. Dysregulation of TRPs, including the TRPM3 family, is likely pertinent in predisposing CFS patients to calcium metabolism perturbations and aligns with symptom presentation.…”

Pharmacology of TRP Channels

“…However, its physiological role is still under investigation. Activation of TRPM3 has been linked to insulin secretion in pancreatic beta-cells (Wagner et al 2008), to vascular smooth muscle cell contraction , and to potentiating glutamatergic transmission in cerebellar Purkinje neurons of developing rats (Zamudio-Bulcock et al 2011). A role in pain transduction has also been reported for TRPM3 (Vriens et al 2011).…”