Table 3.

Calcium Channels and Transporters Important to Neurotransmission and Possible Roles in PFAS Neurotoxicity^a

type	neurological functions	mechanisms related to neurotransmission	PFAS neurotoxicity	source
Calcium Channel Group: High Voltage-Gated
L-type “long-lasting”				42, 50–52
all subtypes (Cav1.2, Cav1.3, and Cav.1.,4)		tonic and slow release of neurotransmitters	subtypes have not been evaluated individually
		CaM/CaMK/CREB transcription-signaling and CaM/Fas/MAPK-signaling inhibits nicotinic signaling to CREB	PFOS and PFOA induce effects on calcium currents and enhance neurotransmission
			studies did not demonstrate complete block of all other calcium channels in the neuronal cells (effect may not be specific to L-type calcium channels)
			studies have demonstrated that PFOS has downstream effects on the CaM/CaMKII/CREB signaling pathway including deficits in neuronal process formation
Cav1.2	regulates working memory, social behavior, and adaptation to novel situations	in cortex and cerebellum: Cavl.2 C-terminus (CCAT) translocates and acts as a transcription factor for NMDA subunits, K+ channel subunits, and gap junction proteins; promotes neurite outgrowth
	in hippocampus: essential for spatial learning and memory.	expression in increased by cocaine exposure
	loss of function associated with psychiatric disorders including depression, bipol	induces calcium influx that drives the release of catecholamines
	required for neuronal circuit formation and amyglala functional disorder, and schizophrenia
Cav1.3	in VTA and nucleus accumbens: involved with cocaine-induced chronic behavioral changes	expression is decreased with cocaine exposure
	increased expression in early stage Parkinson’s disease	in hippocampus: better coupling to CREB compared to Cav1.2
	channel blocker is a potential target for Parkinson’s disease treatment	in striatal spiny neurons: the only channel that couples to CREB
		induces calcium influx that drives the release of catecholamines in substantia nigra dopaminergic neurons: expression and regulation of pacemaking increases with age
Calcium Channel Group: High Voltage-Gated
N-type “neural”			needs evaluation
Cav2.2	regulates working memory, social behavior, and adaptation to novel situations	rapid synaptic neurotransmitter release
	loss of function reduces ethanol consumption and increases activity	involved in GABA release in some cells in the hippocampus
		primary channel for synaptic glutamate release in many brain regions in hippocampus: partial functional compensation when Cav2.1 has lost function
Calcium Channel Group: High Voltage-Gated
P-type/Q-type			needs evaluation
“Purkinje”/“Q after P” Cav2.1	hippocampus: loss of function induces seizures	rapid synaptic neurotransmitter release
	cerebellum: loss of function induces ataxia and seizures	primary channel for synaptic glutamate release in many brain regions
	gain-of-function mutation induces migraines and cortical depression	involved in GABA release of interneurons in the cortex, pyramidal neurons, and many other neurons
Calcium Channel Group: High Voltage-Gated
R-type “residual”			needs evaluation
Cav2.3	loss of function decreases pain sensitivity	rapid synaptic neurotransmitter release
		in hippocampus: partial functional compensation when the Cav2.1 function is lost Calcium Channel Group: Low Voltage-Gated
Calcium Channel Group: Low Voltage-Gated
T-type “transient” Cav3.1, Cav3.2, and Cav3.3	involved in regulating sleep patterns and arousal	drives low-threshold exocytosis of neurotransmitters	needs evaluation
	mutations associated with epilepsy and autism spectrum disorders	key role in regulating the thalmocortical circuit
		induces calcium influx that drives the release of catecholamines
Calcium Channel Group: Ionotropic Glutamate Receptor
AMPA receptor	synaptic plasticity, long-term potentiation, and action potentials	glutamate-dependent activation of the calcium channel	PFOS decreases subunit expression, thus allowing the AMPA-R type that is permeable to calcium	40–42, 49, 90
		calcium or sodium permeability is determined by the GluA2 subunit; AMPA-R allows calcium to penetrate without the GluA2 subunit or if the GluA2 subunit is the unedited GluA2(Q) isomer; the edited GluA2(R) isomer is normally expressed in neurons	PFOS increases intracellular calcium through the AMPA-R
			expression of edited and nonedited GluA2 receptors after PFAS exposure needs evaluation
NMDA receptor	synaptic plasticity, long-term potentiation, and action potentials	produces excitoxicity-induced cell death by C/EBPβ transcriptional activity	PFOS increases intracellular calcium through glutamateactivated NMDA-R, inducing excitotoxicity	38, 39, 41, 43, 54
		glutamate-dependent activation of the calcium channel	PFOS can increase excitoxicity through the NMDA-R using glutamate-independent toxicity, through an unknown mechanism
		inhibited by L-type induced CREB signaling NMDA-induced increases in calcium activate CaMKIIa

^aNeurological functions of voltage-gated calcium channels are summarized from reviews by Dolphin and Lee (2020),⁹⁵ Saravanaraman et al. (2014),⁹¹ Simms and Zamponi (2014),⁹⁶ and Wang and Jin (2012).⁵³ The calcium channels that are primarily linked to PFAS neurotoxicity are the L-type high-voltage gated channels and the NMDA and AMPA glutamate receptors. Nearly all studies on the toxic effects of PFAS exposure on these calcium channels have only tested PFOS and PFOA.^{38–43,50–52,54} There is much to be learned regarding the roles of calcium channels as primary neurotoxic targets. The primary goal of this table is to prompt mechanistic research.