Calmodulin regulates various channels, including several voltage-gated calcium channels (VGCCs), transient receptor potential channels (TRPCs), NMDA receptors, calcium channels dependent on cyclic nucleotides, and those located in the endoplasmic reticulum such as ryanodine receptors and all isoforms of IP3-dependent receptors (Rebas et al. 2012).  It also mediates secretion in animals of small intron-less proteins (Shao and Hegde, 2011).

Animals

Calmodulin of Homo sapiens (P62158)

Calcium and integrin-binding family member 2, CIB2 or KIP2, of 187 aas.  It is a calcium-binding protein critical for proper photoreceptor cell maintenance and function. It plays a role in intracellular calcium homeostasis by decreasing ATP-induced calcium release (Riazuddin et al. 2012, Seco et al. 2016, Patel et al. 2015). It is essential for mechanotransduction. CIB3 (TC# 8.A.82.1.11) is functionally and structurally equivalent to CIB2 (Liang et al. 2021). CIB2 and CIB3 are structurally similar to KChIP proteins, auxiliary subunits of voltage-gated Kv4 channels. CIB2 and CIB3 bind to TMC1/2 through a domain in TMC1/2 flanked by TMSs 2 and 3. The co-crystal structure of the CIB-binding domain in TMC1 with CIB3 revealed that interactions are mediated through a conserved CIB hydrophobic groove, similar to KChIP1 binding of Kv4. Functional studies in mice showed that CIB2 regulates TMC1/2 localization and function in hair cells, processes that are affected by deafness-causing CIB2 mutations. Thus, CIB2 and CIB3 are MET channel auxiliary subunits with striking similarity to Kv4 channel auxiliary subunits (Liang et al. 2021). CIB3 or KIP3 is 61% identical to CIB2 and is the same length. Complexes of vertebrate TMC1/2 and CIB2/3 proteins form hair-cell mechanotransduction cation channels (Giese et al. 2023).

CIB2 of Homo sapiens

Calcium binding protein 1, CABP1, of 370 aas and 0 TMSs. It modulates the calcium-dependent activity of inositol 1,4,5-triphosphate receptors (ITPRs) (Haynes et al. 2004) and inhibits agonist-induced intracellular calcium signaling (Zhou et al. 2005). It also enhances inactivation and does not support calcium-dependent facilitation of voltage-dependent P/Q-type calcium channels (Lee et al. 2002). It causes calcium-dependent facilitation and inhibits inactivation of L-type calcium channels by binding to the same sites as calmodulin in the C-terminal domain of CACNA1C, but  it has an opposite effect on channel function (Zhou et al. 2004). It suppresses the calcium-dependent inactivation of CACNA1D and inhibits TRPC5 channels (Kinoshita-Kawada et al. 2005) while preventing NMDA receptor-induced cellular degeneration. Complexes of vertebrate TMC1/2 and CIB2/3 proteins form hair-cell mechanotransduction cation channels (Giese et al. 2023).

CABP1 of Homo sapiens

Calpain-1 (two subunits): CPNL1 (catalytic subunit)/CPNS1 (small subunit) of 725 and 268 aas, respectively.  Mitochondrial calpain-1 truncates ATP synthase beta subunit (Chukai et al. 2025).  Calpains cleave proteins in a calcium concentration-dependent manner, modulating their intracellular functions. Calpain-1, a member of the calpain family, is localized in the cytosol and mitochondria. Mitochondrial calpain-1 induces mitochondrial dysfunction and apoptosis by cleaving its substrate.

Calpain-2 of Homo sapiens

Calretinin (Calbindin) of 271 aas and no TMS.  Plays a role in the regulation of cytoplasmic calcium concentrations.  It is a calcium-binding protein abundant in auditory neurons.

Calretinin of Homo sapiens

Calmodulin-like protein, CML6, of 154 aas. May regulate calcium-dependent activities in the endoplasmic reticulum lumen or post-ER compartment. Isoform 5 may be involved in the exocytosis of zymogens by pancreatic acini.

CML6 of Arabidopsis thaliana (Mouse-ear cress)

Calmodulin-like protein, CaM, of 151 aas,

CaM of Drosophila melanogaster (Fruit fly)

Uncharacterized protein of 148 aas

UP of Cladophialophora yegresii

Calcineurin B-like protein of 195 aas, CHP1 or CHP. Calcineurin B homologous proteins 1 and 2 activate NHE1 (TC#2.A.36.1.13) (Cottle et al. 2020). It also regulates endocytosis by a plasma membrane ubiquitin ligase adaptor, Rcr1 (Zhu et al. 2020).

CHP1 of Homo sapiens

RCaMP of 432 aas and 0 TMSs. GCaMP, containing a C-terminal CaM (calmodulin) domain, interferes with both gating and signaling of L-type calcium channels (CaV1). GCaMP acts as an impaired apoCaM and Ca²⁺/CaM, both critical to CaV1 (Yang et al. 2018).

RCaMP of Entacmaea quadricolor (Bubble-tip anemone) (Parasicyonis actinostoloides)

Calmodulin-like protein 4 of 205 aas and possibly 2 or 3 N-terminal TMSs.

Calmodulin-like protein 4 of Sinocyclocheilus anshuiensis

Calcium and integrin-binding protein 1, CIB1, CIB, KIP, PAKDCIP, of 191 aas. It is a calcium-binding protein that plays a role in the regulation of numerous cellular processes, such as cell differentiation, cell division, cell proliferation, cell migration, thrombosis, angiogenesis, cardiac hypertrophy and apoptosis (Armacki et al. 2014).  It forms a heterotrimeric complex with TMC6 (TC# 1.A.17.4.10) and TMC8 (TC# 1.A.17.4.11), stabilizing the complex (Wu et al. 2020).

CIB1 of Homo sapiens

Kv channel-interacting protein 4 (KChIP4) (A-type potassium channel modulatory protein 4) (Calsenilin-like protein) (Potassium channel-interacting protein 4).  These proteins have N-terminal variants due to the presence of multiple start sites (Jerng and Pfaffinger 2014). Novel long interspersed element-1 (L1) retrotransposon insertions in several genes associated with seizures/epilepsy, including a de novo somatic L1 retrotransposition in KCNIP4, have been identified (Doyle et al. 2021).

Animals

KCNIP4 of Homo sapiens

Salt overly sensitive-3, SOS3 of 222 aas.  The salt stress-induced SALT-OVERLY-SENSITIVE (SOS) pathway in Arabidopsis thaliana involves the perception of a calcium signal by the SOS3 and SOS3-like CALCIUM-BINDING PROTEIN8 (SCaBP8) calcium sensors, which then interact with and activate the SOS2 protein kinase (9.B.106.3.4), forming a complex at the plasma membrane that activates the SOS1 Na⁺/H⁺ exchanger (2.A.36.7.6) (Lin et al. 2014).

Plants

SOS3 of Arabidopsis thaliana

The K+-voltage-gated ion channel interacting protein, KCNIP2 or KCHIP2 protein of 270 aas, a regulator and subunit of K⁺ channels such as Kv4.3 and Kv1.4 as well as cardiac L-type Ca⁺ channels (Thomsen et al. 2009; Hovind et al. 2011; Wang et al. 2013).  It plays a role in the regulation of ion channel function and stress responses (Hudlikar et al. 2021).

KCHIP2 of Homo sapiens

Calsenilin (KCHIP3, KCNIP3, CSEN, DREAM) of 256 aas and 0 TMSs.  Regulatory subunit of Kv4/D (Shal)-type voltage-gated rapidly inactivating A-type potassium channels, such as KCND2/Kv4.2 and KCND3/Kv4.3. Modulates channel expression at the cell membrane, gating characteristics, inactivation kinetics and rate of recovery from inactivation in a calcium-dependent and isoform-specific manner (Jerng and Pfaffinger 2008). Interacts with TRPV1 (TC# 1.A.4.2.1) and alleviates inflammatory hyperalgesia (Tian et al. 2018). IQM-266 is a chemical that may allow a better understanding of DREAM physiological role as well as modulation of neuronal I A in pathological processes (Peraza et al. 2019). Overexpression of calsenilin enhances gamma-secretase activity (TC# 4.G.1) (Jo et al. 2005).

Calsenilin of Homo sapiens

Kv channel-interacting protein, KChIP-1 or KCNIP1 of 227 aas and 0 TMSs.  It is a regulatory subunit of Kv4/D (Shal)-type voltage-gated rapidly inactivating A-type potassium channels. It regulates channel density and influences inactivation kinetics and the rate of recovery from inactivation in a calcium-dependent and isoform-specific manner. In vitro, it modulates KCND1/Kv4.1 and KCND2/Kv4.2 currents and increases the presence of KCND2 at the cell surface (Wang et al. 2007; An et al. 2000).

KChIP-1 of Homo sapiens

Recoverin, of 200 aas, has been mplicated in the pathway from retinal rod guanylate cyclase to rhodopsin. It may be involved in the inhibition of the phosphorylation of rhodopsin in a calcium-dependent manner as the calcium-bound recoverin prolongs the photoresponse. It is a myristoylated protein, and myristoylation causes membrane association (Brand and Koch 2018).

Recoverin of Homo sapiens

Hippocalcin, a Ca²⁺-binding protein of 193 aas. It may play a role in the regulation of voltage-dependent calcium channels (Helassa et al. 2017). It may also play a role in cyclic-nucleotide-mediated signaling through the regulation of adenylate and guanylate cyclases.  Parkin-null brains show dysregulation of this calcium homeostasis factor as well as ATP1A2 and GNA11, reflected by altered firing of noradrenergic neurons (Key et al. 2019).  Variants in Ano3 (TC# 1.A.17.1.20) and other Ca²⁺ regulating proteins like hippocalcin have been identified as  causes of dystonia (Ousingsawat et al. 2024).

Hippocalcin of Homo sapiens

Guanylyl cyclase-activating protein 2 of 200 aas, GucA1B or Gcap2. It stimulates two retinal guanylyl cyclases (GCs) GUCY2D and GUCY2F when the free calcium ion concentration is low, and inhibits them when the free calcium ion concentration is elevated. This Ca²⁺-sensitive regulation of GCs is a key event in the recovery of the dark state of rod photoreceptors following light exposure. It may be involved in the cone photoreceptor response and recovery in bright light. Light activates a G protein signaling cascade, which closes cGMP-gated channels and decreases Ca²⁺ levels in photoreceptor outer segment because of continuing Ca²⁺ extrusion by NCKXs (Vinberg et al. 2018).

GucA1B of Homo sapiens

45 kDa Ca²⁺-binding protein of 362 aas with an N-terminal TMS, SDF4 or CAB45. Cab45 mediates sorting of a subset of secretory proteins at the trans-Golgi network. In response to Ca²⁺ influx, Cab45 forms oligomers, enabling it to bind a variety of specific cargo molecules (Blank and von Blume 2017). It has an internal repeat involving residues 47 - 163 and residues 210 - 347.

CAB45 of Homo sapiens

Reticulocalbin-2 (calumenin-like protein) of 405 aas and 1 N-terminal TMS. These proteins are characterized by at least one EF-hand calcium binding motif, and they belong to a diverse superfamily of calcium sensors and calcium signal modulators. Most members have 2 active canonical EF hands.

Reticulocalbin-2 of Vigna radiata

EF-hand calcium-binding domain-containing protein 3, EFCAB3, of 438 aas and 0 TMSs (Zhang et al. 2018).

EFCAB3 of Homo sapiens

Aequorin-1 of 196 aas and 0 TMSs. It is a Ca²⁺-dependent bioluminescence photoprotein that displays an emission peak at 470 nm (blue light). Trace amounts of calcium ion trigger the intramolecular oxidation of the chromophore, coelenterazine, into coelenteramide and CO₂ with the concomitant emission of light (). Characteristics of the aequorin-expressing yeast strains appear suitable for its use in expression-based methods directed at cloning Ca²⁺ transporters from mammalian mitochondria and for further examining the interrelationships between mitochondrial and cytoplasmic Ca²⁺ in yeast (Jung et al. 2004).

Aequorin-1 of Aequorea victoria (Water jellyfish) (Mesonema victoria)

N-terminal EF-hand calcium-binding protein 1; Neuronal calcium-binding protein 1 of 351 aas and 0 TMSs. Fluoxetine (Flx) is the most commonly used antidepressant to treat major depressive disorder.  A comparative proteomic approach identified proteome changes in the prefrontal cortex (PFC) cytosolic and non-synaptic mitochondria (NSM)-enriched fractions of adult male Wistar rats following chronic social isolation (CSIS), a rat model of depression.  Flx treatment in CSIS rats downregulated protein involved in oxidative phosphorylation, such as complex III and manganese superoxide dismutase, and upregulated vesicle-mediated transport and synaptic signaling proteins in the cytosol, and neuronal calcium-binding protein 1 in NSM (Filipović et al. 2022).

CaBP of Homo sapiens