Table 2.

Direct regulation of ion channels by G proteins.

G protein		Ion channel	Regulationa	Direct bindingb	Functional testb	Direct recordingb	X-ray crystallography	Cryo-EM
				[Reference]
Heterotrimeric G protein	Gβγ	GIRK2	↑		Whole-cell patch clamp/oocyte53	Lipid bilayer/Pichia pastoris55,56	50
		TRPM3	↓	Co-IP/HEK29351,68,69, BLI, dot blot analysis/Sf9, Escherichia coli51	Whole-cell patch clamp/HEK29351,52,68–70/oocyte53/DRG neuron68–70 Two-electrode voltage clamp/oocyte51,68 Calcium imaging/HEK29368,69/DRG neuron68–70	Inside-out patch clamp/HEK29352,70, /oocyte68	51	52
		TRPM1	↓	Co-IP/HEK29372	Whole-cell patch clamp/retinal bipolar cell72, HEM, HEK29375 Calcium imaging/HEM, HEK29375
		CaV2.2	↓		Whole-cell patch clamp/sympathic neuron76 /DRG neuron77
	Gαi3	TRPC5	↑	Co-IP/HEK29379	Whole-cell patch clamp/HEK29379,87	Inside-out patch clamp/HEK29379		79
	Gαi2	TRPC4	↑	Co-IP/HEK29387,95, pull-down assay/E. Coli87	Whole-cell patch clamp/HEK29387,95 Calcium imaging/HEK29395
	Gαq	TRPC1/4 TRPC1/5	↑	Co-IP/HEK29398	Whole-cell patch clamp/HEK29398
	Gαq	TRPM8	↓	Co-IP, pull-down assay/HEK293, DRG neuron99 Pull-down assay/HEK293100	Whole-cell patch clamp/HEK29399,100	Inside-out patch clamp/HEK29399
	Gαo	TRPM1	↓	Co-IP/HEK29372	Whole-cell patch clamp/retinal bipolar cell72
	Gαo	GIRK1/GIRK2	↑	Co-IP/rat brain tissue Pull-down assay/E. Coli104		Inside-out patch clamp/pyramidal cell103
	Gαs	CaV1.2	↑			lipid bilayer/cardiac sarcolemmal vesicle105 /skeletal muscle T-tubule106,107
	Gαs	NaV1.5	↓			Inside-out patch clamp/ventricular myocyte108
Small G protein	RhoA	TRPV4	↓	Co-IP, co-incubation, pull-down assay/HEK293, MN1 NMR spectroscopy/E. Coli113	Calcium imaging, FRET assay/stable cell line113			16–18
	Rab11a	TRPV5/TRPV6	↓	Yeast two-hybrid, Co-IP, pull-down assay/oocyte, E. Coli115
	RGKs	CaV1/CaV2	↓	Co-IP, pull-down assay/COS-1, HEK293119,127, co-IP/HEK293120,123,124,126, Yeast two-hybrid, co-IP, pull-down assay/HEK293122	Whole-cell patch clamp, FRET assay/HEK293, tsA201120,127 Whole-cell patch clamp, calcium imaging/PC12, MIN6, BHK, oocyte122,126 Whole-cell patch clamp/HEK293, HIT-T15, ventricular myocyte123–125

^aArrows in the table indicate either up- or downregulation of ion channel activities by G proteins in each case.

^bReferences for direct binding include co-immunoprecipitation (co-IP), BLI and binding affinity assays such as pulldown and yeast two hybrid, among other techniques. References for functional tests using expression systems include whole-cell patch-clamp recordings, Ca²⁺ imaging and Förster resonance energy transfer (FRET) assays. References for direct recordings include data from inside-out patch-clamp recordings and lipid bilayer systems. DRG, dorsal root ganglion.